Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c

ABSTRACT

This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid(benzyl-cyano-methyl)-amides of formula 1 
     
       
         
         
             
             
         
       
     
     and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

FIELD OF INVENTION

This invention relates to substituted2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid(benzyl-cyano-methyl)-amides of formula 1

and their use as inhibitors of Cathepsin C, pharmaceutical compositionscontaining the same, and methods of using the same as agents fortreatment and/or prevention of diseases connected with dipeptidylpeptidase I activity, e.g. respiratory diseases.

BACKGROUND INFORMATION

-   -   WO2004110988 discloses peptidyl nitrile inhibitors as        dipeptidyl-peptidase I (DPPI) inhibitors for the treatment of a        series of diseases.    -   WO2009074829 and WO2010142985 also disclose peptidyl nitrile        inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the        treatment asthma, COPD or allergic rhinitis.

BRIEF SUMMARY OF THE INVENTION

Dipeptidyl-aminopeptidase I (DPPI or Cathepsin C; EC3.4.141), is alysosomal cysteine protease capable of removing dipeptides from theamino terminus of protein substrates. DPPI was first discovered byGutman and Fruton in 1948 (J. Biol. Chem. 174: 851-858, 1948). The cDNAof the human enzyme has been described in 1995 (Paris et al.; FEBS Lett369: 326-330, 1995). The DPPI protein is processed into a matureproteolytically active enzyme consisting of a heavy chain, a lightchain, and a propeptide that remains associated with the active enzyme(Wolters et al.; J. Biol. Chem. 273: 15514-15520, 1998). Whereas theother cysteine Cathepsins (e.g. B, H, K, L and S) are monomers, DPPI isa 200-kD tetramer with 4 identical subunits, each composed of the 3different polypeptide chains. DPPI is constitutively expressed in manytissues with highest levels in lung, kidney, liver and spleen (Kominamiet al.; Biol. Chem. Hoppe Seyler 373: 367-373, 1992). Consistent withits role in the activation of serine proteases from hematopoetic cells,DPPI is also relatively highly expressed in neutrophils, cytotoxiclymphocytes, natural killer cells, alveolar macrophages and mast cells.Recent data from DPPI deficient mice suggest that, besides being animportant enzyme in lysosomal protein degradation, DPPI also functionsas the key enzyme in the activation of granule serine proteases incytotoxic T lymphocytes and natural killer cells (granzymes A and B;Pham et al.; Proc. Nat. Acad. Sci. 96: 8627-8632, 1999), mast cells(chymase to and tryptase; Wolter et al.; J. Biol. Chem. 276:18551-18556, 2001), and neutrophils (Cathepsin G, elastase andproteinase 3; Adkison et al.; J. Clin. Invest. 109: 363.371, 2002). Onceactivated, these proteases are capable of degrading variousextracellular matrix components, which can lead to tissue damage andchronic inflammation.

Thus, inhibitors of Cathepsin C could potentially be useful therapeuticsfor the treatment of neutrophil-dominated inflammatory diseases such aschronic obstructive pulmonary disease (COPD), pulmonary emphysema,asthma, multiple sclerosis, and cystic fibrosis (Guay et al.; Curr.Topics Med. Chem. 10: 708-716, 2010; Laine and Busch-Petersen; ExpertOpin. Ther. Patents 20: 497-506, 2010). Rheumatoid arthritis is alsoanother chronic inflammatory disease where DPPI appears to play a role.Neutrophils are recruited to the site of joint inflammation and releaseCathepsin G, elastase and proteinase 3, proteases which are believed tobe responsible for cartilage destruction associated with rheumatoidarthritis. Indeed, DPPI deficient mice were protected against acutearthritis induced by passive transfer of monoclonal antibodies againsttype II collagen (Adkison et al.; J. Clin. Invest. 109: 363.371, 2002).

In light of the role DPPI plays in activating certain pro-inflammatoryserine proteases, it seems desirable to prepare compounds that inhibitits activity, which thereby inhibit downstream serine protease activity.It has been surprisingly found that the bicyclic compounds of thepresent invention possess potent Cathepsin C activity, high selectivityagainst other Cathepsins, e.g. Cathepsin K, and in general desirablepharmacokinetic properties.

DETAILED DESCRIPTION OF THE INVENTION

A compound of formula 1

wherein

-   R¹ is independently selected from H, C₁₋₆-alkyl-, halogen, HO—,    C₁₋₆-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN— and (C₁₋₆-alkyl)₂N—,    C₁₋₆-alkyl-C(O)HN—;-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected from    -   R^(2.1);    -   aryl-; optionally substituted with one, two or three residues        independently selected from R^(2.1); optionally substituted with        one R^(2.3);    -   C₅₋₁₀-heteroaryl-; containing one, two, three or four        heteroatoms independently selected from S, S(O), S(O)₂, O and N,        wherein carbon atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.1); wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.2); wherein a carbon atom of the ring is optionally        substituted with one R^(2.3); a nitrogen atom of the ring is        optionally substituted with one R^(2.4); and    -   C₅₋₁₀-heterocyclyl-; containing one, two, three or four        heteroatoms independently selected from S, S(O), S(O)₂, O and N,        wherein the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one, two or three or four R^(2.1);        wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.2); wherein a carbon atom of the ring is optionally        substituted with one R^(2.3) or one R^(2.5); a nitrogen atom of        the ring is optionally substituted with one R^(2.4) or    -   R² and R⁴ are together with two adjacent carbon atoms of the        phenyl ring a 5- or 6-membered aryl or heteroaryl, containing        one, two or three heteroatoms independently selected from S,        S(O), S(O)₂, O and N, wherein carbon atoms of the ring are        optionally and independently from each other substituted with        one, two or three R^(2.1); wherein nitrogen atoms of the ring        are optionally and independently from each other substituted        with one, two or three R^(2.2);    -   R^(2.1) is independently selected from among H, halogen, NC—,        O═, HO—, H-A-, H-A-C₁₋₆-alkylene-, R^(2.1.1)-A-, C₁₋₆-alkyl-A-,        C₃₋₈-cycloalkyl-A-, C₁₋₆-haloalkyl-A-,        R^(2.1.1)—C₁₋₆-alkylene-A-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,        C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-,        R^(2.1.1)—C₁₋₆-alkylene-A-C₁₋₆-alkylene-,        R^(2.1.1)-A-C₁₋₆-alkylene-, HO—C₁₋₆-alkylene-A-,        HO—C₁₋₆-alkylene-A-C₁₋₆-alkylene-, C₁₋₆-alkyl-O—C₁₋₆-alkylene-A-        and C₁₋₆-alkyl-O—C₁₋₆-alkylene-A-C₁₋₆-alkylene-;        -   R^(2.1.1) is independently selected from            -   aryl-; optionally substituted independently from each                other with one, two or three R^(2.1.1.1);            -   C₅₋₁₀-heteroaryl-; containing one, two, three or four                heteroatoms independently selected from S, S(O), S(O)₂,                O and N, wherein carbon atoms of the ring are optionally                and independently from each other substituted with one,                two or three R^(2.1.1.1); wherein nitrogen atoms of the                ring are optionally and independently from each other                substituted with one, two or three R^(2.1.1.2);            -   C₅₋₁₀-heterocyclyl-; containing one, two, three or four                heteroatoms independently selected from S, S(O), S(O)₂,                O and N, wherein the ring is fully or partially                saturated, wherein carbon atoms of the ring are                optionally and independently from each other substituted                with one, two or three or four R^(2.1.1.1); wherein                nitrogen atoms of the ring are optionally and                independently from each other substituted with one, two                or three R^(2.1.1.2);        -   R^(2.1.1.1) is independently selected from among halogen,            HO—, O═, C₁₋₆-alkyl-, C₁₋₆-alkyl-O—, C₁₋₆-haloalkyl-,            C₁₋₆-haloalkyl-O— and C₃₋₈-cycloalkyl-;        -   R^(2.1.1.2) is independently selected from among O═,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            C₁₋₆-alkyl-O—C₁₋₆-alkyl-, H(O)C—, C₁₋₆-alkyl-(O)C—,            tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;    -   R^(2.2) is independently selected from among H-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,        C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,        C₁₋₆-alkyl-S(O)₂—, C₁₋₆-alkyl-C(O)— and R^(2.1.1)-A-;    -   R^(2.3) and R⁴ are together selected from    -   among —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—,        —N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, R^(2.3), R^(2.3),        —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—, —C(R^(2.3.2))₂—O—,        —O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—,        —N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-;        -   R^(2.3.1) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and,            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        -   R^(2.3.2) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.4) and R⁴ are together selected from    -   among —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,        —S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—,        —S(O)₂—, —C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—,        —C(R^(2.4.2))₂N(R^(2.4.1))—, —N(R^(2.4.1))C(R^(2.4.2))₂— and        —C₁₋₄-alkylene-; and        -   R^(2.4.1) is independently selected from H, C₁₋₆-alkyl-,            C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)HN—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        -   R^(2.4.2) is independently selected from H, C₁₋₆-alkyl-,            C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.5) and R⁴ are together selected from —C(R^(2.5.1))═,        ═C(R^(2.5.1))— and —N═; and        -   R^(2.5.1) is independently selected from H, C₁₋₆-alkyl-,            C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R³ is H or F;-   R⁴ is independently selected from F, Cl, phenyl-H₂C—O—, HO—,    C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,    C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,    C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-;-   A is a bond or independently selected    -   from —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—,        —N(R⁵)S(O)₂—, —S(O)(═N R⁵)—N(R⁵)—, —N(R⁵)(NR⁵═)    -   S(O)—, —S(═NR⁵)₂—N(R⁵)—, —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—,    -   —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, —S(═NR⁵)—,        —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is independently selected from H, C₁₋₆-alkyl- and NC—;-   or a salt thereof.

Preferred Embodiments

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.a)and R^(1.a) is independently selected from H, C₁₋₄-alkyl-, F and HO—.

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.b)and R^(1.b) is H.

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.c)and two R^(1.c) are together —CH₂—.

Preferred are the above compounds of formula 1, wherein R² is R^(2.a)and R^(2.a) is R^(2.1).

Preferred are the above compounds of formula 1, wherein R² is R^(2.b)and R^(2.b) is R^(2.1.a).

Preferred are the above compounds of formula 1, wherein R² is R^(2.c)and R^(2.c) is aryl-; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3).

Preferred are the above compounds of formula 1, wherein R² is R^(2.d)and R^(2.d) is phenyl; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3).

Preferred are the above compounds of formula 1, wherein R² is R^(2.d)and R^(2.d) is phenyl; optionally substituted with one, two or threeresidues independently selected from R^(2.1) and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H, halogen, NC—,    O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,    C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,    C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,    C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2);        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from halogen, HO—, O═,        C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O—        and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from O═, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,        H(O)C—, C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and        tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R² is R^(2.g)and R^(2.g) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H, halogen, NC—,    O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,    C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,    C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,    C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1); wherein nitrogen atoms of the ring are optionally            and independently from each other substituted with one, two            or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from halogen, HO—, O═,        C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O—        and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from O═, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,        H(O)C—, C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and        tetrahydropyranylmethyl; and-   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected from    H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—,    R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.e)and R^(2.e) is C_(5 or 6)-heteroaryl-, containing one, two, three orfour heteroatoms independently selected from S, S(O), S(O)₂, O and N,wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein nitrogenatoms of the ring are optionally and independently from each othersubstituted with one, two or three R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.f)and R^(2.f) is bicyclic C₇₋₁₀-heteroaryl-, each containing one, two,three or four heteroatoms independently selected from S, S(O), S(O)₂, Oand N, wherein carbon atoms of the ring are optionally and independentlyfrom each other substituted with one, two or three R^(2.1); whereinnitrogen atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.2); wherein a carbon atomof the ring is optionally substituted with one R^(2.3); a nitrogen atomof the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.g)and R^(2.g) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4)

Preferred are the above compounds of formula 1, wherein R² is R^(2.h)and R^(2.h) is selected from pyrazole, thiopheneand furane, whereincarbon atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.i)and R^(2.i) is selected from C₆-heterocyclyl- and C₇₋₁₀-heterocyclyl-,each containing one, two, three or four heteroatoms independentlyselected from S, O and N and the ring is fully or partially saturated,wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein nitrogenatoms of the ring are optionally and independently from each othersubstituted with one, two or three R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3) or one R^(2.5); anitrogen atom of the ring is optionally substituted with one R^(2.4)

Preferred are the above compounds of formula 1, wherein R² is R^(2.j)and R^(2.j) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3) or one R^(2.5); anitrogen atom of the ring is optionally substituted with one R^(2.4)

Preferred are the above compounds of formula 1, wherein R² is R^(2.j)and R^(2.j) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H, halogen, NC—,    O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,    C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,    C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,    C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1) is selected from        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from halogen, HO—, O═,        C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O—        and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from O═, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,        H(O)C—, C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and        tetrahydropyranylmethyl; and-   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected from    H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—,    R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.k)and R^(2.k) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3) or one R^(2.5); anitrogen atom of the ring is optionally substituted with one R^(2.4)

Preferred are the above compounds of formula 1, wherein R² is R^(2.l)and R^(2.l) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.m)and R^(2.m) is together with R⁴ and two adjacent carbon atoms of thephenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, twoor three heteroatoms independently selected from S, S(O), S(O)₂, O andN, preferably pyrazole, naphtene, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1), wherein possibly available nitrogen atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.2).

Preferred are the above compounds of formula 1, wherein R² is R^(2.n)and R^(2.n) is selected from aryl-, pyrazole, thiophene and furane;wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3); a nitrogenatom of the ring is optionally substituted with one R^(2.4); or R^(2.n)is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.o)and R^(2.o) is selected from aryl-, pyrazole, thiophene and furane;wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3); a nitrogenatom of the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.p)and R^(2.p) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.q)and R^(2.q) is selected from among the substituents (a1) to (q1)

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other are substituted with R^(2.2);

Particularly preferred R^(2.q) is substituent (a1) or (c1), wherein

carbon atoms of the ring are optionally and independently from eachother substituted with one, two, three or four R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other are substituted with R^(2.2)

Particularly preferred R^(2.q) denotes a substituent selected from thegroup (a1) to (q1), wherein carbon atoms of the ring are optionally andindependently from each other substituted with a group selected fromamong ═O, Me, MeSO₂—, Me-piperazinyl-SO₂—, morpholinyl, —CN and F, andpossibly available nitrogen atoms of the ring are optionally andindependently from each other is substituted with Me₂N—CH₂—CH₂—,F₂CH—CH₂—, —CH₃ and tetrahydrofuranyl.

Preferred are the above compounds of formula 1, wherein R² is R^(2.s)and R^(2.s) is Phenyl-R^(2.3), wherein the phenyl ring is optionallysubstituted with one or two residues R^(2.1), wherein

-   -   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H, halogen,        NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,        C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,        R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,        R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,        HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-        and C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and        -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from            -   aryl-, optionally substituted independently from each                other with one, two or three residues independently                selected from R^(2.1.1.1);            -   C₅₋₁₀-heteroaryl-, containing one, two, three or four                heteroatoms selected independently from S, S(O), S(O)₂,                O and N, wherein carbon atoms of the ring are optionally                and independently from each other substituted with one,                two or three R^(2.1.1); wherein nitrogen atoms of the                ring are optionally and independently from each other                substituted with one, two or three R^(2.1.1.2);            -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four                heteroatoms selected independently from S, S(O), S(O)₂,                O and N, and the ring is fully or partially saturated,                wherein carbon atoms of the ring are optionally and                independently from each other substituted with one, two                or three R^(2.1.1); wherein nitrogen atoms of the ring                are optionally and independently from each other                substituted with one, two or three R^(2.1.1.2); and        -   R^(2.1.1.1) is independently selected from halogen, HO—, O═,            C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,            C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and        -   R^(2.1.2) is independently selected from O═, C₁₋₄-alkyl-,            C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,            H(O)C—, C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and            tetrahydropyranylmethyl.            and R^(2.s) and R⁴ together denote a group (r1),

wherein the N-atom is optionally substituted with —R^(2.2), wherein

-   -   R^(2.2) is independently selected from H-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,        C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,        C₁₋₆-alkyl-S(O)₂—, C₁₋₆-alkyl-C(O)— and R^(2.1.1)-A-.

Particularly preferred are the above compounds of formula 1, wherein R²is R^(2.s) and R^(2.s) is Phenyl-R^(2.3),

wherein the phenyl ring is optionally substituted with one or tworesidues independently selected from F and —CN,and R^(2.s) and R⁴ together denote a group (r1), wherein the N-atom isoptionally substituted with —CH₃,

Particularly preferred are the above compounds of formula 1, wherein

R¹ is H,

R³ is H or F, preferably F,and

R² is R^(2.s) and R^(2.s) is Phenyl-R^(2.3),

-   -   wherein the phenyl ring is optionally substituted with one or        two residues independently selected from F and —CN,    -   and R^(2.s) and R⁴ together denote a group (r1), wherein the        N-atom is optionally substituted with —CH₃;

Particularly preferred are the above compounds of formula 1, whereinR^(2.s) and R⁴ together denote a group (r1), optionally substituted asdescribed above, in meta and para position of the phenyl ring.

Preferred are the above compounds of formula 1, wherein R² is R^(2.r)and R^(2.r) is selected from among the substituents (a2) to (w2) or

R² together with R⁴ denotes a group selected from among (a3) to (e3).

Particularly preferred R^(2.r) is substituent (a2) or (c2).

Particularly preferred R² is substituted Phenyl-R^(2.3) wherein R²together with R⁴ denotes a group selected from among (a3), (b3), (c3),(d3) and (e3).

Preferred are the above compounds of formula 1, wherein R^(2.1) isR^(2.1.a) and R^(2.1.a) is selected from H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from

-   -   aryl-, optionally substituted independently from each other with        one, two or three residues independently selected from        R^(2.1.1.1);    -   C₅₋₁₀-heteroaryl-, containing one, two, three or four        heteroatoms selected independently from S, S(O), S(O)₂, O and N,        wherein carbon atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.1.1); wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.1.1.2)    -   and    -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four        heteroatoms selected independently from S, S(O), S(O)₂, O and N        and the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one, two or three R^(2.1.1.1); wherein        nitrogen atoms of the ring are optionally and independently from        each other are substituted with one, two or three R^(2.1.1.2);        and    -   R^(2.1.1) is independently selected from halogen, HO—, O═,        C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O—        and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from O═, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,        H(O)C—, C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and        tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.b) and R^(2.1.1.b) is phenyl or selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1.1.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.1.1.2); and

-   R^(2.1.1.1) is independently selected from halogen, HO—, O═,    C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O— and    C₃₋₆-cycloalkyl-; and-   R^(2.1.1.2) is independently selected from O═, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—,    C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and    tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.c) and R^(2.1.1.c) is phenyl or selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1.1.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.1.1.2); and

-   R^(2.1.1.1) is independently selected from F, Cl, Me, MeO— and    cyclopropyl-; and-   R^(2.1.1.2) is independently selected from Me,    tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.2) isR^(2.1.2.a) and R^(2.1.2.a) is selected from H, NC—, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene- and(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.1.2) isR^(2.1.2.b) and R^(2.1.2.b) is selected from H, C₁₋₄-alkyl-, andC₃₋₆-cycloalkyl-;

Preferred are the above compounds of formula 1, wherein R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected fromH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—,R^(2.1.1)-A-;

Preferred are the above compounds of formula 1, wherein R^(2.2) isR^(2.2.b) and R^(2.2.b) is together with R⁴ selected from —C(O)—,—S(O)—, —S(O)₂—, —C(R^(2.1.2))═C(R^(2.1.2))— and —C₁₋₄-alkylene-;

Preferred are the above compounds of formula 1, wherein R^(2.3) istogether with R⁴ a group R^(2.3.a) and R^(2.3.a) is selected

from —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—, —N(R^(2.3.1))C(O)—,—S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—, —C(O) O—, —OC(O)—, —C(O)—,—S(O)—, —S(O)₂—, —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—,—C(R^(2.3.2))₂—O—, —O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—,—N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-; and

-   R^(2.3.1) is independently selected from H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R^(2.3.2) is independently selected from H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.4) istogether with R⁴ a group R^(2.4.a) and R^(2.4.a) is selected

from —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,—S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—, —S(O)₂—,—C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—, —C(R^(2.4.2))₂N(R^(2.4.1))—,—N(R^(2.4.1))C(R^(2.4.2))₂— and —C₁₋₄-alkylene-; and

-   R^(2.4.1) is independently selected from H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R^(2.4.2) is independently selected from H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene-, (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.5) istogether with R⁴ a group R^(2.5.a) and R^(2.5.a) is selected from—C(R^(2.5.1))═, ═C(R^(2.5.1))— and —N═; and

-   R^(2.5.1) is independently selected from H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.m)and R^(2.m) is together with R⁴ and two adjacent carbon atoms of thephenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, twoor three heteroatoms independently selected from S, S(O), S(O)₂, O andN, wherein carbon atoms of the ring are optionally and independentlyfrom each other substituted with one, two or three R^(2.1), whereinpossibly available nitrogen atoms of the ring are optionally and toindependently from each other substituted with one, two or threeR^(2.2); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H, halogen, NC—,    O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,    C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,    C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,    C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2);        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1); wherein nitrogen atoms of the ring are optionally            and independently from each other substituted with one, two            or three R^(2.1.1.2) and    -   R^(2.1.1.1) is independently selected from halogen, HO—, O═,        C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O—        and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from O═, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,        H(O)C—, C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and        tetrahydropyranylmethyl; and-   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected from    H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—,    R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.n)and R^(2.n) is selected from aryl-, pyrazole, thiophene and furane;wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3); a nitrogenatom of the ring is optionally substituted with one R^(2.4); or R^(2.n)is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H, halogen, NC—,    O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,    C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,    C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,    C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from halogen, HO—, O═,        C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O—        and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from O═, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,        H(O)C—, C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and        tetrahydropyranylmethyl; and-   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected from    H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—,    R^(2.1.1)-A-; and-   R^(2.3) is together with R⁴ a group R^(2.3.a) and R^(2.3.a) is    selected    -   from —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—,        —N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—,        —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—, —C(R^(2.3.2))₂—O—,        —O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—,        —N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-; and    -   R^(2.3.1) is independently selected from H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.3.2) is independently selected from H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        and-   R^(2.4) is together with R⁴ a group R^(2.4.a) and R^(2.4.a) is    selected    -   from —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,        —S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—,        —S(O)₂—, —C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—,        —C(R^(2.4.2))₂N(R^(2.4.1))—, —N(R^(2.4.1))C(R^(2.4.2))₂— and        —C₁₋₄-alkylene-; and    -   R^(2.4.1) is independently selected from H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.4.2) is independently selected from H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        and-   R^(2.5) is together with R⁴ a group R^(2.5.a) and R^(2.5.a) is    selected from —C(R^(2.5.1))═, ═C(R^(2.5.1))— and —N═; and    -   R^(2.5.1) is independently selected from H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein

R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;R² is selected from

-   -   R^(2.1);    -   phenyl-; optionally substituted with one or two residues        independently selected from R^(2.1); optionally substituted with        one R^(2.3);    -   C₅-heteroaryl-; containing two or three independently selected        from S, O and N, wherein carbon atoms of the ring are optionally        and independently from each other substituted with one R^(2.1);        wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one R^(2.2);    -   monocyclic C₆-heterocyclyl containing one or two nitrogen atoms,        wherein the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one R^(2.1); wherein nitrogen atoms of        the ring are optionally and independently from each other        substituted with one R^(2.2); and    -   bicyclic C_(9 or 10)-heterocyclyl-; containing one, two, three        or four heteroatoms to independently selected from S(O)₂, O and        N, wherein the ring is fully or partially saturated, wherein        carbon atoms of the ring are optionally and independently from        each other substituted with one, two or three R^(2.1); wherein        nitrogen atoms of the ring are optionally and independently from        each other substituted with one R^(2.2);    -   R^(2.1) is independently selected from halogen, NC—, O═, H-A-,        H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,        C₃₋₆-cycloalkyl-A-, R^(2.1)—C₁₋₄-alkylene-A-,        C₁₋₄-alkyl-A-C₁₋₄-alkylene-, and        HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-;        -   R^(2.1.1) is independently selected from            -   phenyl-; and            -   C_(5 or 6)-heterocyclyl-; containing one or two                heteroatoms independently selected from O and N, wherein                the ring is fully or partially saturated, wherein                nitrogen atoms of the ring are optionally and                independently from each other substituted with one                C₁₋₄-alkyl-;    -   R^(2.2) is independently selected from H-A-C₁₋₄-alkylene-,        C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene- and C₁₋₄-alkyl-C(O)—;    -   R^(2.3) and R⁴ are together a group selected    -   from —N(R^(2.3.1))—, —C(O)N(R^(2.3.2))— and —N(R^(2.3.1))C(O)—;        -   R^(2.3.1) is independently selected from H and H₃C—;

R³ is H or F; R⁴ is R^(4.b) and R^(4.b) is F;

A is a bond or independently selected

-   -   from —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)₂— and —N═(O)(R⁵)S—;        R⁵ is independently selected from H and C₁₋₄-alkyl-;        or a salt thereof.

Preferred are the above compounds of formula 1, wherein R² is selectedfrom the

Table 1R²—Embodiments of the invention for R², R^(2.1), R^(2.1.1),R^(2.2), R^(2.3), R^(2.4) and R^(2.5) (if present):

E# R² R^(2.1) R^(2.1.1) R^(2.2) R^(2.3-5)  1 R^(2.a) R^(2.1) R^(2.1.1.a)—  2 R^(2.a) R^(2.1) R^(2.1.1.b) —  3 R^(2.a) R^(2.1) R^(2.1.1.c) —  4R^(2.b) R^(2.1.a) R^(2.1.1.a) —  5 R^(2.b) R^(2.1.a) R^(2.1.1.b) —  6R^(2.b) R^(2.1.a) R^(2.1.1.c) —  7 R^(2.c) R^(2.1.a) R^(2.1.1.a) — —  8R^(2.c) R^(2.1.a) R^(2.1.1.b) — —  9 R^(2.c) R^(2.1.a) R^(2.1.1.c) — —10 R^(2.c) R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 11 R^(2.c) R^(2.1.a)R^(2.1.1.c) — R^(2.4.a) 12 R^(2.c) R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 13R^(2.d) R^(2.1.a) R^(2.1.1.a) — — 14 R^(2.d) R^(2.1.a) R^(2.1.1.b) — —15 R^(2.d) R^(2.1.a) R^(2.1.1.c) — — 16 R^(2.d) R^(2.1.a) R^(2.1.1.c) —R^(2.3.a) 17 R^(2.d) R^(2.1.a) R^(2.1.1.c) — R^(2.4.a) 18 R^(2.d)R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 19 R^(2.e) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 20 R^(2.e) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 21 R^(2.e)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 22 R^(2.f) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 23 R^(2.f) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 24 R^(2.f)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 25 R^(2.g) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 26 R^(2.g) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 27 R^(2.g)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 28 R^(2.h) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 29 R^(2.h) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 30 R^(2.h)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 31 R^(2.e) R^(2.1.a) R^(2.1.1.c) —R^(2.3.a) 32 R^(2.e) R^(2.1.a) R^(2.1.1.c) — R^(2.4.a) 33 R^(2.e)R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 34 R^(2.g) R^(2.1.a) R^(2.1.1.c) —R^(2.3.a) 35 R^(2.g) R^(2.1.a) R^(2.1.1.c) — R^(2.4.a) 36 R^(2.g)R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 37 R^(2.h) R^(2.1.a) R^(2.1.1.c) —R^(2.3.a) 38 R^(2.h) R^(2.1.a) R^(2.1.1.c) — R^(2.4.a) 39 R^(2.h)R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 40 R^(2.i) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 41 R^(2.i) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 42 R^(2.i)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 43 R^(2.j) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 44 R^(2.j) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 45 R^(2.j)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 46 R^(2.k) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 47 R^(2.k) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 48 R^(2.k)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 49 R^(2.l) R^(2.1.a) R^(2.1.1.a)R^(2.2.a) — 50 R^(2.l) R^(2.1.a) R^(2.1.1.b) R^(2.2.a) — 51 R^(2.l)R^(2.1.a) R^(2.1.1.c) R^(2.2.a) —

For a better understanding of the Table 1R²—Embodiments of the inventionexample (E#) 21, can also be read as a group R², wherein

-   R² is R^(2.e) and R^(2.e) is C_(5 or 6)-heteroaryl-, containing one,    two, three or four heteroatoms independently selected from S, S(O),    S(O)₂, O and N, wherein carbon atoms of the ring are optionally and    independently from each other substituted with one, two or three    R^(2.1); wherein nitrogen atoms of the ring are optionally and    independently from each other substituted with one, two or three    R^(2.2); and    -   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H, halogen,        NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1)-A-,        C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,        R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,        R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,        HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-        and C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and        -   R^(2.1.1) is R^(2.1.1.c) and R^(2.1.1.c) is phenyl or            selected from

-   -   -   -   wherein carbon atoms of the ring are optionally and                independently from each other substituted with one, two                or three R^(2.1.1.1) wherein possibly available nitrogen                atoms of the ring are optionally and independently from                each other substituted with R^(2.1.1.2); and            -   R^(2.1.1.1) is independently selected from F, Cl, Me,                MeO— and cyclopropyl-; and            -   R^(2.1.1.2) is independently selected from Me,                tetrahydrofuranylmethyl- and tetrahydropyranylmethyl;                and

    -   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected        from H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,        C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)—, R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R³ is R^(3.a)and R^(3.a) is H.

Preferred are the above compounds of formula 1, wherein R³ is R^(3.b)and R^(3.b) is F.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.a)and R^(4.a) is selected from F, Cl, phenyl-H₂C—O—, HO—, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and C₁₋₄-haloalkyl-O—.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.b)and R^(4.b) is F; preferably in ortho position.

Preferred are the above compounds of formula 1, wherein A is A^(a) andA^(a) is a bond or independently selected

from —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—, —C(O)O—,—OC(O)—, —C(O)—, —S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and —N═(O)(R⁵)S—and R⁵ is R^(5.a) and R^(5.a) is independently selected from H,C₁₋₄-alkyl- and NC—.

Preferred is a compound of formula 1, wherein

-   R¹ is independently selected from H, C₁₋₄-alkyl-, halogen, HO—,    C₁₋₄-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— and    C₁₋₆-alkyl-C(O)HN—;-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or    19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,    36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48, 49, 50,    51;-   R³ is H or F;-   R⁴ is independently selected from F, Cl, phenyl-H₂C—O—, HO—,    C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,    C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,    C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-;-   A is a bond or independently selected    -   from —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—,        —N(R⁵)S(O)₂—, —S(O)(═N R⁵)—N(R⁵)—, —N(R⁵)(NR⁵═),    -   S(O)—, —S(═NR⁵)₂—N(R⁵)—, —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—,    -   —C(O)O—, —OC(O)—, —C(O)—, —S(O)—,    -   S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—,        —(R⁵N═)(O)S— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from H, C₁₋₆-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.a) and R^(1.a) is independently selected from H,    C₁₋₄-alkyl-, F and HO—.-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or    19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,    36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48, 49, 50,    51;-   R³ is H or F;-   R⁴ is R^(4.a) and R^(4.a) is F, Cl, phenyl-H₂C—O—, HO—, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and    C₁₋₄-haloalkyl-O—;-   A is a bond or independently selected    -   from —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—,        —N(R⁵)S(O)₂—, —S(O)(═N R⁵)—N(R⁵)—, —N(R⁵)(NR⁵═)    -   S(O)—, —S(═NR⁵)_(z)—N(R⁵)—, —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—,        —C≡C—,    -   —C(O)O—, —OC(O)—, —C(O)—, —S(O)—,    -   S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—,        —(R⁵N═)(O)S— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from H, C₁₋₆-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.a) and R^(1.a) is independently selected from H,    C₁₋₄-alkyl-, F and HO—.-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29,    30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47 and 48;-   R³ is H or F;-   R⁴ is R^(4.a) and R^(4.a) is selected from F, Cl, phenyl-H₂C—O—,    HO—, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—    and C₁₋₄-haloalkyl-O—;-   A is A^(a) and A^(a) is a bond or independently selected    -   from —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from H,    C₁₋₄-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29,    30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47 and 48;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is F;-   A is A^(a) and A^(a) is a bond or independently selected    -   from —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from H,    C₁₋₄-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29,    30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47 and 48;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is F;-   A is A^(a) and A^(a) is a bond or independently selected    -   from —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from H,    C₁₋₄-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected from    -   R^(2.1);    -   phenyl-; optionally substituted with one or two residues        independently selected from R^(2.1); optionally substituted with        one R^(2.3);    -   C₅-heteroaryl-; containing two or three independently selected        from S, O and N, wherein carbon atoms of the ring are optionally        and independently from each other substituted with one R^(2.1);        wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one R^(2.2);    -   monocyclic C₆-heterocyclyl containing one or two nitrogen atoms,        wherein the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one R^(2.1); wherein nitrogen atoms of        the ring are optionally and independently from each other        substituted with one R^(2.2); and    -   bicyclic C_(9 or 10)-heterocyclyl-; containing one, two, three        or four heteroatoms independently selected from S(O)₂, O and N,        wherein the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one, two or three R^(2.1); wherein        nitrogen atoms of the ring are optionally and independently from        each other substituted with one R^(2.2);    -   R^(2.1) is independently selected from halogen, NC—, O═, H-A-,        H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,        C₃₋₆-cycloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,        C₁₋₄-alkyl-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-;        preferably F, NC—, O═, H-A-, H-A-CH₂—, R^(2.1.1)-A-, H₃C-A-,        H₃C—CH₂-A-, Cyclopropyl-A-, R^(2.1.1)—CH₂—CH₂-A-,        R^(2.1.1)—CH₂-A-, H₃C-A-CH₂—CH₂— and HO—C₄-alkylene-A-CH₂—;        -   R^(2.1.1) is independently selected from            -   phenyl-; and            -   C_(5 or 6)-heterocyclyl-; containing one or two                heteroatoms independently selected from O and N, wherein                the ring is fully or partially saturated, wherein                nitrogen atoms of the ring are optionally and                independently from each other substituted with one                C₁₋₄-alkyl-; preferably H₃C—;    -   R^(2.2) is independently selected from H-A-C₁₋₄-alkylene-,        C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-C(O)—; preferably        H-A-CH₂—, H-A-CH₂—CH₂—, cyclopropyl-, H₃C-A-CH₂—CH₂—,        R^(2.1.1)-A-CH₂— and H₃C—C(O)—;    -   R^(2.3) and R⁴ are together a group selected    -   from —N(R^(2.3.1))—, —C(O)N(R^(2.3.2))— or —N(R^(2.3.1))C(O)—;        -   R^(2.3.1) is independently selected from H and H₃C—;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is F;-   A is a bond or independently selected    -   from —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)₂— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from H or C₁₋₄-alkyl-;-   or a salt thereof.

Preferred are the above compounds of formula 1, wherein

R³ is R^(3.a) and R^(3.a) is H, and R⁴ is R^(4.b) and R^(4.b) is F;

Particularly preferred are the above compounds of formula 1, wherein

R³ is H, R⁴ is F and

R² is R^(2.q) and R^(2.q) is selected from among the substituents (a1)to (q1).

Particularly preferred are the above compounds of formula 1, wherein

R³ is F and

R² and R⁴ together denote a group selected from among (r1) to (t1).

Preferably (a1) to (q1) or (r1) to (t1) are independently substituted bya substituent selected from among

═O, Me, MeSO₂—, Me-piperazinyl-SO₂—, morpholinyl, furanyl,Me₂N—CH₂—CH₂—, F₂CH—CH₂—, —CN and F.

Preferred are the compounds of formula I, wherein the compounds areselected from the group consisting of examples 2, 3, 6, 16, 43, 155,193, 249, 250, 254, 283, 284, 322, 323, 324, 325, 326, 328, 329, 330,331, 333, 342, 343, 351, 352, 353, 354, 355, 356, 357, 358 and 359.

Particularly preferred are the compounds of formula I, wherein thecompounds are selected from the group consisting of examples 322, 323,324, 325 and 326.

Preferred are the above compounds of formula 1, in its enantiomericallypure form of formula 1′

wherein R¹, R², R³ and R⁴ have the above mentioned meaning.

USED TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms.

In general in single groups like HO, H₂N, S(O), S(O)₂, NC (cyano), HOOC,F₃C or the like, the skilled artisan can see the radical attachmentpoint(s) to the molecule from the free valences of the group itself. Forcombined groups comprising two or more subgroups, the last namedsubgroup is the radical attachment point, for example, the substituent“aryl-C₁₋₄-alkyl-” means an aryl group which is bound to aC₁₋₄-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

Alternatively “*” indicates within a chemical entity the binding site,i.e. the point of attachment.

In case a compound of the present invention is depicted in form of achemical name and as a is formula in case of any discrepancy the formulashall prevail. An asterisk is may be used in sub-formulas to indicatethe bond which is connected to the core molecule as defined.

Many of the followings terms may be used repeatedly in the definition ofa formula or group and in each case have one of the meanings givenabove, independently of one another.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

The expressions “prevention”, “prophylaxis”, “prophylactic treatment” or“preventive treatment” used herein should be understood synonymous andin the sense that the risk to develop a condition mentioned hereinbeforeis reduced, especially in a patient having elevated risk for saidconditions or a corresponding anamnesis, e.g. elevated risk ofdeveloping metabolic disorder such as diabetes or obesity or anotherdisorder mentioned herein. Thus the expression “prevention of a disease”as used herein means the management and care of an individual at risk ofdeveloping the disease prior to the clinical onset of the disease. Thepurpose of prevention is to combat the development of the disease,condition or disorder, and includes the administration of the activecompounds to prevent or delay the onset of the symptoms or complicationsand to prevent or delay the development of related diseases, conditionsor disorders. Success of said preventive treatment is reflectedstatistically by reduced incidence of said condition within a patientpopulation at risk for this condition in comparison to an equivalentpatient population without preventive treatment.

The expression “treatment” or “therapy” means therapeutic treatment ofpatients having already developed one or more of said conditions inmanifest, acute or chronic form, including symptomatic treatment inorder to relieve symptoms of the specific indication or causal treatmentin order to reverse or partially reverse the condition or to delay theprogression of the indication as far as this may be possible, dependingon the condition and the severity thereof. Thus the expression“treatment of a disease” as used herein means the management and care ofa patient having developed the disease, condition or disorder. Thepurpose of treatment is to combat the disease, condition or disorder.Treatment includes the administration of the active compounds toeliminate or control the disease, condition or disorder as well as toalleviate the symptoms or complications associated with the disease,condition or disorder.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

As used herein the term “prodrug” refers to (i) an inactive form of adrug that exerts its effects after metabolic processes within the bodyconverting it to a usable or active form, or (ii) a substance that givesrise to a pharmacologically active metabolite, although not itselfactive (i.e. an inactive precursor).

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative, carrier or precursor of the parent compound or active drugsubstance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). Such prodrugs either havemetabolically cleavable or otherwise convertible groups and are rapidlytransformed in vivo to yield the parent compound, for example, byhydrolysis in blood or by activation via oxidation as in case ofthioether groups. Most common prodrugs include esters and amide analogsof the parent compounds. The prodrug is formulated with the objectivesof improved chemical stability, improved patient acceptance andcompliance, improved bioavailability, prolonged duration of action,improved organ selectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity). Ingeneral, prodrugs themselves have weak or no biological activity and arestable under ordinary conditions. Prodrugs can be readily prepared fromthe parent compounds using methods known in the art, such as thosedescribed in A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991,particularly Chapter 5: “Design and Applications of Prodrugs”; Design ofProdrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical andOcular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods inEnzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985,particularly pp. 309-396; Burger's Medicinal Chemistry and DrugDiscovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol,diethanolamine(2,2′-iminobis(ethanol)), diethylamine,2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine,N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine(2,2′,2″-nitrilotris(ethanol)), tromethamine, zinchydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoricacid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citricacid, cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, is oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like. (also seePharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66,1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer selected from 2, 3, 4,5 or 6, either alone or in combination with another radical denotes anacyclic, saturated, branched or linear hydrocarbon radical with 1 to n Catoms. For example the term C₁₋₅-alkyl embraces the radicals H₃C—,H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—,H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer selected from 2, 3,4, 5 or 6, preferably 4 or 6, either alone or in combination withanother radical, denotes an acyclic, straight or branched chain divalentalkyl radical containing from 1 to n carbon atoms. For example the termC₁₋₄-alkylene includes —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—,—C(CH₃)₂—, —CH(CH₂CH₃)—, —CH(CH₃)—C H₂—, —CH₂—CH(CH₃)—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—CH₂—,—CH₂—CH(CH₃)—CH₂—, —CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂—, —CH(CH₃)—CH(CH₃)—,—CH₂—CH(CH₂CH₃)—, —CH(CH₂ CH₃)—CH₂—, —CH(CH₂CH₂CH₃)—, —CH(CH(CH₃))₂— and—C(CH₃)(CH₂CH₃)—.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer selected from 4,5, 6, 7 or 8, preferably 4, 5 or 6, either alone or in combination withanother radical denotes a cyclic, saturated, unbranched hydrocarbonradical with 3 to 8 C atoms. For example the term C₃₋₈-cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl.

By the term “halo” added to a “alkyl”, “alkylene” or “cycloalkyl” group(saturated or unsaturated) is such a alkyl or cycloalkyl group whereinone or more hydrogen atoms are replaced by a halogen atom selected fromamong fluorine, chlorine or bromine, preferably fluorine and chlorine,particularly preferred is fluorine. Examples include: H₂FC—, HF₂C—,F₃C—.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second five-or six-membered, carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl.

The term “C₅₋₁₀-heterocyclyl” means a saturated or unsaturated mono- orpolycyclic-ring systems including aromatic ring system containing one ormore heteroatoms independently selected from N, O or S(O)_(r), whereinr=0, 1 or 2, consisting of 5 to 10 ring atoms wherein none of theheteroatoms is part of the aromatic ring. The term “heterocyclyl” isintended to include all the possible isomeric forms. Thus, the term“heterocyclyl” includes the following exemplary structures which are notdepicted as radicals as each form may be attached through a covalent(single or double) bond to any atom so long as appropriate valences aremaintained:

The term “C₅₋₁₀-heteroaryl” means a mono- or polycyclic-ring systemscontaining one or more heteroatoms independently selected from N, O orS(O)_(r), wherein r=0, 1 or 2, consisting of 5 to 10 ring atoms whereinat least one of the heteroatoms is part of aromatic ring. The term“heteroaryl” is intended to include all the possible isomeric forms.Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Preparation General Synthetic Methods

The invention also provides processes for making a compound of FormulaI. In all methods, unless specified otherwise, R¹, R² and n in theformulas below shall have the meaning of R¹, R² and n in Formula 1 ofthe invention described herein above.

Optimal reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC) or LC-MS, ifdesired, and intermediates and products may be purified bychromatography to on silica gel, HPLC and/or by recrystallization. Theexamples which follow are illustrative and, as recognized by one skilledin the art, particular reagents or conditions could be modified asneeded for individual compounds without undue experimentation. Startingmaterials and intermediates used, in the methods below, are eithercommercially available or easily prepared from commercially availablematerials by those skilled in the art.

A compound of Formula V, VII and IX may be made by the method outlinedin Scheme 1:

As illustrated in Scheme 1, a compound of Formula II, wherein PGrepresents a protecting group (e.g. tert-butoxycarbonyl), may be reactedwith an aqueous ammonia solution, using standard literature proceduresfor the formation of an amide. For example, in the presence of a basesuch as N-methyl-morpholine or N-ethyl-morpholine and an activatingagent such as O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate(TBTU). The reaction is conveniently carried out in a suitable solventsuch as N,N-dimethylformamide. Standard peptide to coupling reactionsknown in the art (see for example M. Bodanszky, 1984, The Practice ofPeptide Synthesis, Springer-Verlag) may be employed in these syntheses.

Dehydration of an amide such as in a compound of Formula III or FormulaIX to the corresponding nitrile of Formula IV or VII may be carried outby use of a dehydration agent such as (methoxycarbonylsulfamoyl)triethylammonium hydroxide, in a suitable solvent such as dichloromethane (DCM).

Reacting an acid of Formula VI using standard literature procedures forthe formation of an amide, for example in the presence of a base such asN,N-diisopropylethylamine (DIPEA) and an activating agent such as HATUor TBTU, with an amine of Formula V or VIII in a suitable solvent,provides a compound of Formula VII or IX. Standard peptide couplingreactions known in the art (see for example M. Bodanszky, 1984, ThePractice of Peptide Synthesis, Springer-Verlag) may be employed in thesesyntheses.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M.Wuts, Wiley-Interscience. For example, for the deprotection oftert-butoxycarbonyl, an acid such as formic acid, trifluoroacetic acid,p-toluenesulfonic acid or HCl may be used in a suitable solvent such aswater, DCM or dioxane. Another method to is deprotecttert-butoxycarbonyl is the reaction with trimethyliodosilane ortrimethylchlorosilane in combination with sodium iodide in anappropriate solvent like acetonitrile, DMF or DCM.

During the reaction sequences depicted in Scheme 1 and Scheme 2 ahydroxy group (X═OH) can be converted to a trifluoromethanesulfonylgroup (X═OTf) at any level. Especially, a compound IX with X═OH istransformed to the appropriate triflate (X═OTf) by reaction withN,N-bis-(trifluoromethanesulfonyl) aniline, or trifluoromethanesulfonylchloride or anhydride, in the presence of an organic base e.g.triethylamine, morpholine, piperidine, DIPEA in an appropriate anhydroussolvent, e.g. DCM.

As illustrated in Scheme 2, (transition) metal catalyzed reaction of acompound of Formula VII or IX wherein X is I, Br, Cl or OTf, provides acompound of Formula X or XI. For example, reaction with a boronic acidor the corresponding boronic acid ester, in a suitable solvent such asacetonitrile, in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as K₂CO₃ provides a compound of Formula X or XI.Alternatively, reaction of a compound of Formula VII or IX, wherein X isI, Br, Cl or OTf with a tributyl(vinyl)tin reagent in the presence of asuitable catalyst such as bis-(triphenylphosphin)-palladiumchloride, ina suitable solvent such as dimethylformamide (DMF) and if desirable inthe presence of an additive such as tetraethylammonium chloride providescompounds of Formula X or XI. Further, reaction of a compound of FormulaVII or IX, wherein X is I or Br, may be reacted with an amine in thepresence of a suitable catalyst such as Cu(I)I and a suitable base suchas caesium carbonate and a suitable promotor such as L-proline providesa compound of Formula X or XI.

In an inversed fashion compounds of formula VII or IX (X: I, Br, Cl,OTf) can be converted into the corresponding boronic acid derivativesVIIa or IXa, wherein R can be H or lower alkyl independently and theresidues R can form a ring. For example, VII or IX can be reacted withbis-pinacolato-diboron in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as potassium acetate or sodium, potassium or cesiumcarbonate or phosphate, in a suitable solvent such as dioxan,dimethylformamide (DMF), or dichloromethane (DCM) to yield the boronicesters VIIa or IXa, respectively. These can be reacted with appropriatearomatic halides in analogy as above to yield the desired couplingproducts of formula X or XI.

Further, as illustrated in Scheme 2, reaction of a compound of FormulaVII or IX, wherein X is N₃ with an alkyne in the presence of a suitablecatalyst such as copper(II)sulfate pentahydrate and a suitable reducingagent such as L-ascorbic acid in a suitable solvent such as dimethylsulfoxide (DMSO)/water provides a compound of Formula X or XI.

Further modifications of compounds of Formula X, XI and I by methodsknown in the art and illustrated in the Examples below, may be used toprepare additional compounds of the invention. Dehydration of an amideof Formula XI to the corresponding nitrile of Formula X may be carriedout by use of a dehydration agent such as(methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, in a suitablesolvent such as DCM.

As illustrated in Scheme 3, (transition) metal catalyzed reaction of acompound of Formula IV wherein X is I, Br, Cl or OTf, provides acompound of Formula XII. For example, reaction with a boronic acid orthe corresponding boronic acid ester, in a suitable solvent such asacetonitrile, in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as K₂CO₃ provides a compound of Formula XII.

An acid of Formula VI using standard literature procedures for theformation of an amide, for example in the presence of a base such asDIPEA and an activating agent such as HATU or TBTU, can be reacted withan amine of Formula XII in a suitable solvent. Standard peptide couplingreactions known in the art (see for example M. Bodanszky, 1984, ThePractice of Peptide Synthesis, Springer-Verlag) may be employed in thesesyntheses. Deprotection of functional groups is described in ‘ProtectiveGroups in Organic Synthesis’, T. W. Greene and P. G. M. Wuts,Wiley-Interscience. For example, for the deprotection oftert-butoxycarbonyl, an acid such as formic acid, p-toluenesulfonicacid, trifluoroacetic acid or HCl may be used in a suitable solvent suchas water, DCM or dioxane and can be performed on the crude amidecoupling product to provide a compound of Formula I. Another method todeprotect tert-butoxycarbonyl is the reaction with trimethyliodosilaneor trimethylchlorosilane in combination with sodium iodide in anappropriate solvent like acetonitrile, DMF or DCM.

As illustrated in Scheme 4, amino nitrile derivatives of Formula XIIIcan be converted to substituted amino nitriles of Formula V viaalkylation to compounds of Formula XIV, followed by deprotection of theamino group. During the alkylation step a suitable base is used in anappropriate solvent, using a benzylation agent XV with an appropriateleaving group like Cl, Br, or sulfonates. Especially useful is the useof sodium hydroxide as base in water and DCM under phase transferconditions using benzyltrimethylammonium chloride as described forexample by Naidu et al, WO2011/46873. The protective group is removedunder acidic conditions, e.g. aq. HCl in dioxan. The amino nitrile V isfurther processed as depicted in Scheme 1.

As illustrated in Scheme 5, nitro compounds of formula XV can be reducedto anilines of formula XVI by catalytic hydrogenation under conditions,where the nitrile group is still stable. Better suited are reagents likesodium dithionite, SnCl₂ or iron in a suitable solvent like water,methanol, ethanol, acetonitrile or ethyl acetate.

Reacting of 2-halo-benzoic acid, especially 2-iodo-benzoic acid usingstandard literature procedures for the formation of an amide, forexample in the presence of a base such as N,N-diisopropylethylamine(DIPEA) and an activating agent such as HATU or TBTU, with an amine ofFormula XVI in a suitable solvent, provides a compound of Formula XVII.Standard peptide coupling reactions known in the art (see for example M.Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) maybe employed in these syntheses.

The benzoic amide group as in Formula XVII can be protected by an acidlabile group, especially by alkoxymethyl or silylalkoxymethyl groups asmentioned for example in ‘Protective Groups in Organic Synthesis’, T. W.Greene and P. G. M. Wuts, Wiley-Interscience. Especially useful is theuse of 2-trimethylsilylethoxymethylchloride as alkylating agent afterhaving removed the amide proton by a strong base such as NaH in an inertsolvent like DMF, THF or dioxan. The products are compounds of theformula XVIII.

Cyclisation of compounds like formula XVIII can be performed with theaid of a palladium catalyst likePd(PPh₃)-4(tetrakis(triphenylphosphine)palladium(0) and a base likepotassium acetate or sodium, potassium or cesium carbonate or phosphate,especially sodium carbonate in a suitable solvent, e.g. DMF, preferrablyunder elevated temperature. This results in the formation of compound ofthe formula XIXa and XIXb, which can be separated or processed furtheras a mixture.

Compounds like XIXa or XIXb or a mixture thereof can be deprotected inacidic medium. Deprotection of functional groups is described in‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M.Wuts, Wiley-Interscience. For example, an acid such as formic acid,p-toluenesulfonic acid, trifluoroacetic acid or HCl may be used in asuitable solvent such as water, DCM or dioxane and can be performed onthe crude amide coupling product to provide a compound of Formula XXaand XXb. Another method to deprotect first the tert-butoxycarbonyl isthe reaction with trimethyliodosilane or trimethylchlorosilane incombination with sodium iodide in an appropriate solvent likeacetonitrile, DMF or DCM. After that the trimethylsilylmethoxymethylgroup can be removed in acidic medium as mentioned above, especiallywith formic acid again leading to compounds of the formula XXa and XXb.

SYNTHETIC EXAMPLES

The following are representative compounds of the invention which can bemade by the general synthetic schemes, the examples, and known methodsin the art. Starting materials and intermediates were eithercommercially available and purchased from catalogues of AATPHARM, ABCR,ACROS, ACTIVATE, ALDRICH, ALFA, ALLICHEM, ANICHEM, ANISYN, ANISYN Inc.,APAC, APOLLO, APOLLO-INTER,

ARKPHARM, ARKPHARMINC, ASIBA PHARMATECH, ATOMOLE, BACHEM, BEPHARM,BIOFOCUS, BIOGENE, BORON-MOL, BOROPHARM, CHEMBRIDGE, CHEMCOLLECT,CHEMFUTURE, CHEMGENX, CHEMIMPEX, CHESS, COMBI-BLOCKS, COMBI-PHOS,DLCHIRAL, EGA, E-MERCK, EMKA-CHEMIE, ENAMINE, EPSILON, FLROCHEM, FLUKA,FOCUS, FRONTIER, ISOCHEM, JW PHARMLAB, KINGSTONCHEM, LANCASTER,MANCHESTER, MANCHESTER ORGANICS, MAYBRIDGE, MAYBR-INT, MERCACHEM, MERCK,MILESTONE, MOLBRIDGE, NETCHEM, OAKWOOD, PHARMABRIDGE, PLATTE, RIEDEL DEHAEN, SMALL-MOL, SPECS, SPECTRA GROUP LIMITED, INC, SYNCHEM OHG,SYNCHEM-INC, SYNCOM, TCI, VIJAYA PHARMA, WAKO, WUXIAPPTEC or weresynthesized according to literature or as described below in “Synthesisof starting materials/educts”

“Liquid chromatography-mass spectroscopy (LCMS) retention time andobserved m/z data for the compounds below are obtained by one of thefollowing methods:

LC-MS Method 001_CA07 Device-Description Waters Acquity with DAD and MSDColumn Waters Sunfire C18 Column Dimension 2.1 × 50 mm Particle Size 2.5μm Gradient/Solvent % Sol [H₂O % Sol [Acetonitrile Flow Temp Time [min]0.1% TFA] 0.08% TFA] [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 0.75 0.0100.0 1.5 60.0 0.85 0.0 100.0 1.5 60.0 LC-MS Method 002_CA03Device-Description Agilent 1100 with DAD and MSD Column Waters SunfireC18 Column Dimension 3.0 × 30 mm Particle Size 2.5 μm Gradient/Solvent %Sol [H₂O Flow Temp Time [min] 0.1% TFA] % Sol [Acetonitrile [ml/min] [°C.] 0.0 99.0 1.0 2.0 60.0 0.9 0.0 100.0 2.0 60.0 1.1 0.0 100.0 2.0 60.0LC-MS Method 002_CA07 Device-Description Waters Acquity with 3100 MSColumn Waters XBridge BEH C18 Column Dimension 3.0 × 30 mm Particle Size1.7 μm Gradient/Solvent % Sol [H₂O % Sol Flow Temp Time [min] 0.1%NH4OH] [Acetonitrile [ml/min] [° C.] 0.0 95.0 5.0 1.5 60 0 0.7 0.1 99.91.5 60.0 0.8 0.1 99.9 1.5 60.0 0.81 95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.560.0 LC-MS Method 003_CA04 Device-Description Agilent 1100 with DAD andMSD Column Waters XBridge C18 Column Dimension 3.0 × 30 mm Particle Size2.5 μm Gradient/Solvent % Sol [H₂O % Sol Flow Temp Time [min] 0.1%NH4OH] [Acetonitrile [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.02.0 60.0 1.4 0.0 100.0 2.0 60.0 LC-MS Method 004_CA01 Device-DescriptionAgilent 1100 with DAD, Waters Autosampler and MSD Column Waters SunfireC18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Gradient/Solvent %Sol [H₂O % Sol Flow Temp Time [min] 0.1% TFA] [Acetonitrile] [ml/min] [°C.] 0.0 98.0 2.0 2.5 60.0 1.5 0.0 100.0 2.5 60.0 1.8 0.0 100.0 2.5 60.0LC-MS Method 004_CA05 Device-Description Waters Acquity with DAD andMSD, CTC Autosampler Column Waters XBridge C18 Column Dimension 3.0 × 30mm Particle Size 2.5 μm Gradient/Solvent % Sol [H₂O % Sol Flow Temp Time[min] 0.1% NH₄OH] [Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.01.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0 LC-MS Method 004_CA07Device-Description Waters Acquity with with 3100 MS Column YMC TriartC18 Column Dimension 2.0 × 30 mm Particle Size 1.9 μm Gradient/Solvent %Sol [H₂O 0.1% % Sol Flow Temp Time [min] NH4OH] [Acetonitrile [ml/min][° C.] 0.0 95.0 5.0 1.5 60.0 0.75 0.1 99.9 1.5 60.0 0.8 0.1 99.9 1.5 600 0.81 95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.5 60.0 LC-MS Method 005_CA01Device-Description Agilent 1100 with DAD, Waters Autosampler andMS-Detector Column Waters Sunfire C18 Column Dimension 3.0 × 30 mmParticle Size 2.5 μm Gradient/Solvent % Sol [H₂O % Sol Flow Temp Time[min] 0.1% TFA] [Acetonitrile [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.20.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0 LC-MS Method V001_003Device-Description Waters Alliance with DAD and MSD Column WatersXBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μmGradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 4 60 0.20 95 5 4 60 1.5 0 100 4 601.75 0 100 4 60 LC-MS Method V001_007 Device-Description Waters Alliancewith DAD and MSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mmParticle Size 3.5 μm Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time[min] 0.1% TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 4 60 1.6 0 100 4 601.85 0 100 4 60 1.9 95 5 4 60 LC-MS Method V003_003 Device-DescriptionWaters Alliance with DAD and MSD Column Waters XBridge C18 ColumnDimension 4.6 × 30 mm Particle Size 3.5 μm Gradient/Solvent % Sol [H₂O,% Sol Flow Temp Time [min] 0.1% NH₃] [Methanol] [ml/min] [° C.] 0.0 95 54 60 0.2 95 5 4 60 1.5 0 100 4 60 1.75 0 100 4 60 LC-MS Method V011_S01Device-Description Waters Alliance with DAD and MSD Column WatersXBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm SolventGradient % Sol [H₂O, % Sol Flow Temp time [min] 0.1% NH₃] [Acetonitril][ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 560 LC-MS Method V012_S01 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Solvent Gradient % Sol [H₂O, % Sol Flow Temp time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 601.7 0 100 5 60 LC-MS Method V018_S01 Device-Description Waters Alliancewith DAD and MSD Column Waters Sunfire C18 Column Dimension 4.6 × 30 mmParticle Size 3.5 μm Solvent Gradient % Sol [H₂O, % Sol Flow Temp time[min] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 560 1.6 0 100 5 60 1.7 0 100 5 60 LC-MS Method W018_S01Device-Description Waters 1525 with DAD and MSD Column Waters SunfireC18 Column Dimension 4.6 × 30 mm Particle Size 2.5 μm Solvent Gradient %Sol [H₂O, % Sol Flow Temp time [min] 0.1% TFA] [Acetonitril] [ml/min] [°C.] 0.0 97 3 4 60 0.15 97 3 3 60 2.15 0 100 3 60 2.20 0 100 4.5 60 2.400 100 4.5 60 LC-MS Method X001_002 Device-Description Waters Acquitywith DAD and MSD Column Waters XBridge BEH C18 Column Dimension 2.1 × 30mm Particle Size 1.7 μm Gradient/Solvent % Sol [H₂O, % Sol Flow TempTime [min] 0.10% TFA] [Methanol] [ml/min] [° C.] 0.0 99 1 1.3 60 0.05 991 1.3 60 1.05 0 100 1.3 60 1.2 0 100 1.3 60 LC-MS Method X001_004Device-Description Waters Acquity with DAD and MSD Column Waters XBridgeC18 Column Dimension 2.1 × 20 mm Particle Size 2.5 μm Gradient/Solvent %Sol [H₂O, % Sol Flow Temp Time [min] 0.10% TFA] [Methanol] [ml/min] [°C.] 0.0 95 5 1.4 60 0.05 95 5 1.4 60 1.00 0 100 1.4 60 1.1 0 100 1.4 60LC-MS Method X002_002 Device-Description Waters Acquity with DAD and MSDColumn Waters Sunfire C18 Column Dimension 2.1 × 30 mm Particle Size 2.5μm Gradient/ Solvent Time % Sol [H2O, % Sol Flow Temp [min] 0.10% TFA][Methanol] [ml/min] [° C.] 0.00 99 1 1.2 60 0.15 99 1 1.2 60 1.10 0 1001.2 60 1.25 0 100 1.2 60 LC-MS Method X011_S02 Device-Description WatersAcquity with DAD and MSD Column Waters XBridge BEH C18 Column Dimension2.1 × 30 mm Particle Size 1.8 μm Solvent Gradient % Sol [H2O, % Sol FlowTemp time [min] 0.1% NH3] [Acetonitril] [rnl/min] [° C.] 0.00 99 1 1.360 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60 LC-MS MethodX011_S03 Device-Description Waters Acquity with DAD and MSD ColumnWaters Xbridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size 1.7 μmSolvent Gradient % Sol [H2O, % Sol Flow Temp time [min] 0.1% NH3][Acetonitril] [ml/min] [° C.] 0.00 95 5 1.3 60 0.02 95 5 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60 LC-MS Method X012_S01 Device-DescriptionWaters Acquity with DAD and MSD Column Waters XBridge BEH C18 ColumnDimension 2.1 × 30 mm Particle Size 1.7 μm Solvent Gradient % Sol [H₂O,% Sol Flow Temp time [min] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.099 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60 LC-MSMethod X012_S02 Device-Description Waters Acquity with DAD and MSDColumn Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size1.7 μm Solvent % Sol Gradient time [H2O, % Sol Flow Temp [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60 LC-MS Method X016_S01 Device-DescriptionWaters Acquity with DAD and MSD Column Waters XBridge BEH Phenyl ColumnDimension 2.1 × 30 mm Particle Size 1.7 μm Solvent Gradient % Sol [H₂O,% Sol Flow Temp time [min] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.099 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60 LC-MSMethod X018_S01 Device-Description Waters Acquity with DAD and MSDColumn Waters Sunfire C18 Column Dimension 2.1 × 30 mm Particle Size 2.5μm Gradient/Solvent % Sol [H₂O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0100 1.5 60 1.10 0 100 1.5 60 LC-MS Method X018_S02 Device-DescriptionWaters Acquity with DAD and MSD Column Waters Sunfire C18 ColumnDimension 2.1 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol [H₂O,% Sol Flow Temp Time [min] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.099 1 1.3 60 0.02 99 1 1 3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60 LC-MSMethod Z001_002 Device-Description Agilent 1200 with DAD and MSD ColumnWaters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5 μmGradient/Solvent % Sol [H₂O, % Sol Flow Temp Time [min] 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 1002.2 60 1.80 0 100 2.2 60 LC-MS Method Z011_S03 Device-DescriptionAgilent 1200 with DAD and MSD Column Waters XBridge C18 Column Dimension3 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol [H₂O, % Sol FlowTemp Time [mm] 0.1% NH3] [Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 600.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MSMethod Z011_U03 Device-Description Agilent 1200 with DAD and MSD ColumnWaters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5 μmGradient/Solvent % Sol [H₂O, % Sol Flow Temp Time [min] 0.1% NH3][Acetonitril] [ml/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MS Method Z012_S04Device-Description Agilent 1200 with DAD and MSD Column Waters XBridgeC18 Column Dimension 3 × 30 mm Particle Size 2.5 μm Gradient/Solvent %Sol [H₂O, % Sol Flow Temp Time [min] 0.1% NH3] [Acetonitril] [ml/min] [°C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 601.40 0 100 3 60 LC-MS Method Z018_S04 Device-Description Agilent 1200with DAD and MSD Column Waters Sunfire C18 Column Dimension 3 × 30 mmParticle Size 2.5 μm Solvent Gradient % Sol [H₂O, % Sol Flow Temp time[min] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 32.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MS MethodZ020_S01 Device-Description Agilent 1200 with DAD and MSD Column WatersSunfire C18 Column Dimension 3 × 30 mm Particle Size 2.5 μm SolventGradient % Sol [H₂O, % Sol Flow Temp time [min] 0.1% FA] [Acetonitril][ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.250 100 3 60 1.40 0 100 3 60 LC-MS Method V001_007 Device-DescriptionWaters Alliance with DA- and MS-Detector Column XBridge C18 ColumnDimension 4.6 × 30 mm Particle Size 3.5 μm Solvent Gradient % Sol [H₂O,% Sol Flow Temp time [min] 0.1% FA] [Methanol] [ml/min] [° C.] 0.0 95 54.0 60 1.6 0 100 4.0 60 1.85 0 100 4.0 60 1.9 95 5 4.0 60 LC-MS MethodI_ADH_15_MEOH_DEA.M Device-Description Agilent 1260 SFC with DAD ColumnDaicel Chiralpak AD-H Column Dimension 4.6 × 250 mm Particle Size 5 μmSolvent % Sol Gradient [Methanol, time % Sol 0.2% Flow Temp Backpressure[min] [scCO₂] Diethylamine] [ml/min] [° C.] [bar] 0.00 85 15 4 40 15010.00 85 15 4 40 150 LC-MS Method I_OJH_10_IPROP_DEA.MDevice-Description Agilent 1260 SFC with DAD Column Daicel ChiralcelOJ-H Column Dimension 4.6 × 250 mm Particle Size 5 μm Solvent % SolGradient [Isopropanol, time % Sol 0.2% Flow Temp Backpressure [min][scCO₂] Diethylamine] [ml/min] [° C.] [bar] 0.00 90 10 4 40 150 10.00 9010 4 40 150 LC-MS Method I_IC_20_MEOH_NH3.M Device-Description Agilent1260 SFC with DAD and MSD Column Daicel Chiralpak IC Column Dimension4.6 × 250 mm Particle Size 5 μm Solvent % Sol Gradient time % Sol [20rnM NH3 in Flow Temp Backpressure [min] [scCO₂] Methanol] [ml/min] [°C.] [bar] 0.00 80 20 4 40 150 10.00 80 20 4 40 150 LC-MS MethodI_ADH_40_MEOH_DEA.M Device-Description Agilent 1260 SFC with DAD ColumnID aicel Chiralpak AD-H Column Dimension 4.6 × 250 mm Particle Size 5 μmSolvent % Sol Gradient [Methanol, time % Sol 0.2% Flow Temp Backpressure[min] [scCO₂] Diethylamine] [ml/min] [° C.] [bar] 0.00 60 40 4 40 15010.00 60 40 4 40 150 LC-MS Method I_ASH_30_10MIN_SS4P.MDevice-Description Berger SFC Analytix with DAD Column Daicel ChiralpakAS-H Column Dimension 4.6 × 250 mm Particle Size 5 μm Solvent % SolGradient time % Sol [Ethanol, 0.2% Flow Temp Backpressure [min] [scCO₂ ]Diethylamine] [ml/min] [° C.] [bar] 0.00 70 30 4 40 120 10.00 70 30 4 40120 LC-MS Method I_OJH_10_MEOH_DEA.M Device-Description Agilent 1260 SFCwith DAD Column Daicel Chiralcel OJ-H Column Dimension 4.6 × 250 mmParticle Size 5 μm Solvent % Sol Gradient [Methanol, time % Sol 0.2%Flow Temp Backpressure [min] [scCO₂] Diethylamine] [ml/min] [° C.] [bar]0.00 90 10 4 40 150 10.00 90 10 4 40 150

Mixture of stereoisomers can be separated on preparative scale by one ofthe following chiral SFC methods. 2x describes two columns switched in arow.

Methode: Chiral SFC A Column: 2x Daicel Chiralpak AD-H 5 μm 20×250 mm

Eluent: 85% scCO₂, 15% Methanol 0.2% DiethylamineFlow: 55 mL/min

Temperature: 40° C. Backpressure: 120 bar Wavelength: 254 nm

Concentration: 52 mg/ml in MethanolInjection volume: 300 μl

Device-Description: Thar MultiGram II Methode: Chiral SFC B Column: 2xChiralcel OJ-H 5 μm, 20×250 mm

Eluent: 90% scCO₂, 10% Isopropanol 0.2% DiethylamineFlow: 60 mL/min

Temperature: 40° C. Backpressure: 150 bar Wavelength: 254 nm

Concentration: 50 mg/ml in MethanolInjection volume: 200 μl

Device-Description: Jasco Rockclaw 150 Methode: Chiral SFC C Column: 2xDaicel Chiralpak AD-H 5 μm, 10×250 mm

Eluent: 85% scCO₂, 15% Methanol 0.2% DiethylamineFlow: 10 mL/min

Temperature: 40° C. Backpressure: 120 bar Wavelength: 254 nm

Concentration: 15 mg/ml in MethanolInjection volume: 100 μl

Device-Description: Thar MiniGram Methode: Chiral SFC D Column: 1xDaicel Chiralpak AD-H, 5 μm, 20×250 mm

Eluent: 60% scCO₂, 40% Methanol 0.2% DiethylamineFlow: 60 mL/min

Temperature: 40° C. Backpressure: 120 bar Wavelength: 254 nm

Concentration: 50 mg/ml in MethanolInjection volume: 400 μl

Device-Description: Thar MultiGram II Methode: Chiral SFC E Column: 2xDaicel Chiralpak AS-H 5 μm, 20×250 mm Eluent: 70% CO₂, 30% Ethanol 0.2%Diethylamine

Flow: 55 mL/min

Temperature: 40° C. Backpressure: 120 bar Wavelength: 254 nm

Concentration: 100 mg/ml in MethanolInjection volume: 200 μl

Device-Description: Thar MultiGram II Methode: Chiral SFC F Column:Daicel Chiralpak IC 5 μm, 20×250 mm

Eluent: 85% scCO₂, 15% EthanolFlow: 60 mL/min

Temperature: 40° C. Backpressure: 150 bar Wavelength: 254 nm

Concentration: 35 mg/ml in MethanolInjection volume: 500 μl

Device-Description: Sepiatec Prep SFC 100 Methode: Chiral SFC G Column:Chiralpak AY-10 μm, 50×300 mm

Eluent: A for CO₂, and B for ethanol: n-heptane=1:1

Gradient: B 10%

Flow: 170 mL/min

Temperature: 38° C. Backpressure: 100 bar Wavelength: 220 nm

Concentration: 300 mg/ml in ethanolInjection volume: 4 mL per injection

Cycletime: 3.5 min

Device-Description: Thar 200 preparative SFC

Synthesis Methods: Method A Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(2-methylisoindolin-5-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 1

Step 1: Synthesis of Intermediate I-1.1

R1 (20.0 g, 55 mmol) is suspended in DCM (400 mL) and a solution of R2(26.4 g, 111 mmol) dissolved in DCM is added. The reaction mixture isstirred for 12 h under argon atmosphere. The reaction mixture is washedwith water. The organic layer is dried over MgSO₄, filtrated andconcentrated. The residue is dissolved in DCM, filtrated by flashchromatography (using solvent mixture cyclohexane/ethyl acetate=70/30)and concentrated to give I-1.1. Yield 97% m/z 287/343 to [M+H]+, rt 1.29min, LC-MS Method X012_S01.

The following intermediate as shown in Table 2 is synthesized in asimilar fashion from the appropriate intermediates:

TABLE 2 m/z LC-MS Intermediate Educt Structure [M + H]+ rt (min) methodI-1.1.1 R1.1

391 1.29 V012_S01

Step 2: Synthesis of Intermediate I-1.2

To I-1.1 (5.80 g, 17 mmol) in anhydrous dioxane (60 mL) R3 (5.20 g, 20mmol) and potassium acetate (4.98 g, 51 mmol) are added. The mixture ispurged with argon,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)) (1.38 g, 1.7 mmol) is added to the mixture and heated to80° C. for 2 h. DCM is added and the mixture is filtrated. The filtrateis diluted with water and extracted with DCM. The organic layer is driedover MgSO₄, filtrated and concentrated. The residue is purified by flashchromatography (cyclohexane/ethyl acetate=8/2) and concentrated. Yield97% m/z 291/335/391 [M+H]+, rt 1.36 min, LC-MS Method V012_S01.

Step 3: Synthesis of Intermediate I-1.3

I-1.2 (1.22 g, 5 mmol) and R4 (2.30 g, 5.9 mmol) are dissolved inacetonitrile (25 mL). Na₂CO₃-solution (2 mol/L, 4.9 mL) and1,1′-Bis(di-tert-butylphosphino)ferrocene-palladium dichloride (319 mg,0.49 mmol) are added. The reaction mixture is stirred at 80° C. for 1 h.The crude mixture is extracted with ethyl acetate, washed with halfsaturated brine. The organic layer is dried over to MgSO₄, filtrated andconcentrated and the residue is purified by reversed phase HPLC. Yield59%, m/z=396 [M+H]+, rt 0.96 min, LC-MS Method V012_S01.

The following intermediates as shown in Table 3 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 3 m/z LC-MS Intermediate Educt Structure of Intermediate [M + H]+rt (min) method I-1.3.1 I-1.1.1, direct coupling with boronic ester R7.3

444 1.21 V018_S01 I-1.3.2 I-1.2

446 1.18 V012_S01 I-1.3.3 I-1.1, direct coupling with boronic ester R7.1

444 1.14 V011_S01

Step 4: Synthesis of Intermediate I-1.4

I-1.3 (1.15 g, 2.91 mmol) is dissolved in acetonitrile. 1.39 gp-toluenesulfonic acid monohydrate is added and stirred for 48 h. Theprecipitate is filtered off, dissolved in ethyl acetate and washed withsaturated NaHCO₃-solution. The organic layer is dried over MgSO₄,filtrated and concentrated. Yield 78%. m/z 296 [M+H]+, rt 1.03 min,LC-MS Method V011_S01.

The following intermediates as shown in Table 4 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 4 m/z LC-MS Intermediate Educt Structure of Intermediate [M + H]+rt (min) method I-1.4.1 I-1.3.1

344 0.76 V018_S01 I-1.4.2 I-1.3.2

346 0.96 V011_S01 I-1.4.3 I-1.3.3

344 0.77 V018_S01

Step 5: Synthesis of Intermediate I-1.5

To R5 (purchased from Aldrich or synthesized in analogy to Tararov etal, Tetrahedron Asymmetry 13 (2002), 25-28) (98 mg, 0.4 mmol) in DMF(1.5 mL) diisopropylethylamine (0.18 mL, 1.0 mmol) and HATU (154 mg, 0.4mmol) are added and the reaction mixture is stirred for 15 min. Thenintermediate I-1.4 (100 mg, 0.3 mmol) is added and the mixture isstirred for 12 h. DCM is added and the mixture is washed with saturatedNa2CO3 solution. The organic layer is dried over MgSO₄, filtrated, andthe residue is concentrated. Then the residue is purified by reversedphase HPLC. Yield 68%, m/z 419/463/518 [M+H]+, rt 1.29 min, LC-MS MethodV011_S01.

The following intermediates as shown in Table 5 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 5 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-1.5.1 I-1.4.1

567 1.24 V018_S01 I-1.5.2 I-1.4.2

569 1.24 V011_S01 I-1.5.3 I-1.4.3

567 1.14 V011_S01

Step 6: Synthesis of Example 1

To I-1.5 (120 mg, 0.23 mmol) in acetonitrile, p-toluenesulfonic acidmonohydrate (110 mg, 0.58 mmol) is added and stirred for 3 d. Thereaction solution is purified by reversed phase HPLC. Yield 47%, m/z 419[M+H]+, rt 1.16 min, LC-MS Method V011_S01.

Method A1 Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-methyl-2-oxo-indolin-6-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 2

Step 1: Synthesis of Intermediate I-2.1

To R5 (7.59 g, 31 mmol) in DCM (300 mL) diisopropylethylamine (4.8 mL,28 mmol) and HATU (11.5 g, 30 mmol) are added and stirred for 25 min.Then R6 (10.4 g, 28 mmol) and diisopropylethylamine (7.2 mL, 42 mmol)are added and stirred for 3 h. The solvent is evaporated, dissolved inethyl acetate and washed with water, 0.5 M HCl and aq. NaHCO3 solution(10%). The organic layer is dried over MgSO₄, filtrated andconcentrated. The residue is purified by flash chromatography (usingsolvent mixture DCM/methanol=95/5). Yield>95%, m/z 484 [M+H]+, rt 1.18min, LC-MS Method V011_S01.

The following intermediates as shown in Table 6 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 6 m/z rt LC-MS Intermediate Structure [M + H]+ (min) methodI-2.1.1

496 0.95 Z018_S04 I-2.1.2

484/486 0.71 X018_S02 I-2.1.3

440 0.55 Z011_S03

Step 2: Synthesis of Intermediate I-2.2

To I-2.1 (12.7 g, 26 mmol) in DCM (130 mL) R2 (12.5 g, 52 mmol) isadded. The reaction mixture is stirred for 12 h. The solvent isevaporated, dissolved in ethyl acetate and washed with water, 0.1 M HCland aq. NaHCO3 solution (5%). The organic layer is dried over MgSO₄ andconcentrated. The residue is recrystallized from DCM and acetonitrile.Yield 64% m/z 466 [M+H]+, rt 1.30 min, LC-MS Method V011_S01.

The following intermediates as shown in Table 7 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 7 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-2.2.1 I-2.1.1

478 1.03 Z018_S04 I-2.2.3 I-2.1.2

466/468 1.27 V011_S01

Synthesis of Intermediate I-2.2.2 Synthesis of tert-butyl(1S,2S,4R)-2-[[(1S)-2-amino-1-[[2,3-difluoro-4-trifluoromethylsulfonyloxy)phenyl]methyl]-2-oxo-ethyl]carbamoyl]-3-azabicyclo[2.2.1]heptane-3-carboxylate

The phenol I-2.1.3 is transformed into the correspondingtrifluoromethanesulfonate I-2.2.2: I.2.1.3 (200 mg, 0.46 mmol) isdissolved in anhydrous DCM (1.5 mL). Triethylamine (95 μL, 0.69 mmol) isadded and the reaction mixture is cooled to 0° C. R18 (179 mg, 0.50mmol) is then added and the mixture was stirred at 0° C. for 90 minutesand additional 12 h at room temperature. The mixture is concentrated andthe residue is purified by reversed phase HPLC. Yield 85%, m/z 472[M+H−BOC]+, rt 0.97 min, LC-MS Method Z011_S03.

Step 3: Synthesis of Intermediate I-2.3

To I-2.2 (5.00 g, 10 mmol) in acetonitrile (100 mL) R7 (3.07 g, 11 mmol)is added. The mixture is purged with argon,1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.70 g,1.1 mmol) and aq. sodium carbonate solution (2 mol/L, 1.07 mL) are addedand the mixture is heated to 70° C. for 3.5 h. Ethyl acetate and waterare added to the reaction mixture. The organic layer is to washed withaq. NaHCO3 solution (5%) and water. The organic layer is dried overMgSO₄ and concentrated. The residue is purified by flash chromatography(cyclohexane/ethyl acetate=1/1). Yield 41% m/z 533 [M+H]+, rt 1.25 min,LC-MS Method V011_S01.

The following intermediates as shown in Table 8 are synthesized in asimilar fashion from the is appropriate intermediates ((R,S)=1:1 mixtureof stereoisomers at the carbon adjacent to the nitrile group):

TABLE 8 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-2.3.1 I-2.2

560 0.76 X018_S01 I-2.3.2 I-2.2

528 0.88 004_CA01 I-2.3.3 I-2.2

470 0.90 004_CA05 I-2.3.4 I-2.2

510 0.87 004_CA05 I-2.3.5 I-2.2

482 0.77 004_CA05 I-2.3.6 I-2.2

468 0.92 004_CA05 I-2.3.7 I-2.2

454 0.82 Z011_S03 I-2.3.8 I-2.2

496 0.82 004_CA05 I-2.3.9 I-2.2

538 1.00 004_CA05 I-2.3.10 I-2.2

470 0.91 004_CA05 I-2.3.11 I-2.2

539 0.66 004_CA05 I-2.3.12 I-2.2

482 0.75 004_CA05 I-2.3.13 I-2.2.1

407 1.03 Z018_S04 I-2.3.14 I-2.2

499 0.86 004_CA05 I-2.3.15 I-2.2

438 [M + H—BOC]+ 0.94 X018_S04 I-2.3.16 I-2.2

552 0.77 004_CA05 I-2.3.17 I-2.2

556 0.91 X018_S04 I-2.3.18 I-2.2

518 0.89 004_CA05 I-2.3.19 I-2.2

482 0.77 004_CA05 I-2.3.20 I-2.2

510 0.86 004_CA05 I-2.3.21 I-2.2

482 0.75 004_CA01 I-2.3.22 I-2.2

496 0.82 004_CA01 I-2.3.23 I-2.2

554 0.68 004_CA05 I-2.3.24 I-2.2.1

530 1.02 Z018_S04 I-2.3.25 I-2.2

512 0.83 004_CA01 I-2.3.26 I-2.2

354 1.02 Z018_S04 I-2.3.27 I-2.2

530 0.91 004_CA01 I-2.3.28 I-2.2

499 0.82 004_CA05 I-2.3.29 I-2.2

395 [M + H—BOC]+ 1.02 Z018_S04 I-2.3.30 I-2.2

560 0.76 X018_S01 I-2.3.31 I-2.2

468 0.9 004_CA01 I-2.3.32 I-2.2.1

397 0.97 Z018_S04 I-2.3.33 I-2.2

431 1.07 Z018_S04 I-2.3.34 I-2.2

512 0.75 004_CA01 I-2.3.35 I-2.2

536 0.89 004_CA05 I-2.3.36 I-2.2

454 0.85 004_CA01 I-2.3.37 I-2.2

468 0.69 004_CA01 I-2.3.38 I-2.2

482 0.78 004_CA01 I-2.3.39 I-2.2.1

411 1.01 Z018_S04 I-2.3.40 I-2.2

354 0.87 Z018_S04 I-2.3.41 I-2.2

514 0.44 004_CA05 I-2.3.42 I-2.2

538 0.76 004_CA01 I-2.3.43 I-2.2

483 0.93 V012_S01 I-2.3.44 I-2.2

536 0.85 004_CA05 I-2.3.45 I-2.2

483 0.81 004_CA05 I-2.3.46 I-2.2

482 0.77 004_CA05 I-2.3.47 I-2.2.1

547 0.83 004_CA05 I-2.3.48 I-2.2.1

519 0.71 004_CA05 I-2.3.49 I-2.2.1

533 0.77 004_CA05 I-2.3.50 I-2.2.1

519 0.89 004_CA05 I-2.3.51 I-2.2.1

540 0.9 004_CA05 I-2.3.52 I-2.2.1

531 0.74 004_CA05 I-2.3.53 I-2.2.1

530 0.81 004_CA05 I-2.3.54 I-2.2.1

555 0.72 004_CA05 I-2.3.55 I-2.2.1

530 0.85 004_CA05 I-2.3.56 I-2.2.1

494 0.79 004_CA05 I-2.3.57 I-2.2.1

569 0.71 004_CA05 I-2.3.58 I-2.2.1

569 0.66 004_CA05 I-2.3.59 I-2.2.1

554 0.79 004_CA05 I-2.3.60 I-2.2.1

502 0.81 004_CA05 I-2.3.61 I-2.2.1

555 0.74 004_CA05 I-2.3.62 I-2.2.1

554 0.79 004_CA05 I-2.3.63 I-2.2.1

511 0.87 004_CA05 I-2.3.64 I-2.2.1

519 0.73 004_CA05 I-2.3.65 I-2.2.1

531 0.71 004_CA05 I-2.3.66 I-2.2.1

545 0.74 004_CA05 I-2.3.67 I-2.2.1

545 0.76 004_CA05 I-2.3.68 I-2.2.1

569 0.79 004_CA05 I-2.3.69 I-2.2.1

568 0.82 004_CA05 I-2.3.70 I-2.2

460 [M + H—BOC]+ 0.97 X018_S04 I-2.3.71 I-2.2

468 [M + H—BOC]+ 1.00 X018_S04 I-2.3.72 I-2.2

577 n.d. n.d. I-2.3.73 I-2.2

561 n.d. n.d. I-2.3.74 I-2.2.2

469 0.89 Z018_S04 I-2.3.75 I-2.2.2

578 0.88 Z018_S04 I-2.3.76 I-2.2.2

455 (M + H—BOC)+ 0.85 Z018_S04 I-2.3.77 I-2.2.2

488 (M + H—BOC) 0.89 Z018_S04 I-2.3.78 I-2.2.2

503 (M + H—BOC)+ 0.89 Z018_S04 I-2.3.79 I-2.2

626 0.54 X012_S01 I-2.3.80 I-2.2

398 (M + H—BOC)+ 0.89 Z018_S04 I-2.3.81 I-2.2

398 (M + H—BOC)+ 0.89 n.d. I-2.3.82 I-2.2

508 0.94 Z018_S04 I-2.3.83 I-2.2

n.d. n.d. n.d.

During the synthesis of intermediates I-2.3.17 and I-2.3.29 the bromide(I-2.2) is transformed into the corresponding dioxaborolane compound.Coupling with aromatic bromides is performed in analogy to the synthesisof intermediate I-1.3 (method A).

Intermediate I-2.3.43 is further processed via hydrogenation before theBOC group is removed (step 4)

To I-2.3.43 (90 mg, 0.19 mmol) in methanol (10 mL) Pd/C (10%, 20 mg) isadded. The reaction mixture is stirred under hydrogen (50 psi) for 3 h.Then the mixture is filtered and concentrated. The crude product iscarried on with step 4. Yield>95%

In analogy the following intermediates as shown in Table 9 are prepared.

TABLE 9 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) methodI-2.3.43.2 I-3.2.78

517 0.47. X012_S02 I-2.3.43.3 I-2.3.83

561 n.d. n.d.

Intermediates I-2.3.74-78 and I-2.3.43.2 are converted to thecorresponding nitriles in analogy to step 2 of method A1 to yield thecompounds in the following Table 10.

TABLE 10 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-2.3.74.1 I-2.3.74  

451 [M + H − BOC]+ 0.98 Z018_S01 I-2.3.75.1 I-2.3.75  

460 (M + H+) − BOC 0.96 Z018_S04 I-2.3.76.1 I-2.3.76  

437 (M + H − BOC)+ 0.93 Z018_S04 I-2.3.77.1 I-2.3.77  

470 (M + H − BOC)+ 0.96 Z018_S04 I-2.3.78.1 I-2.3.78  

485 (M + H − BOC)+ 0.96 Z018_S04 I-2.3.79.1 I-2.3.43.2

499 0.54 Z018_S02

The intermediate I-2.3.7 is combined with appropriate halogenides oracid chlorides before (in step 4) the BOC group is removed

To I-2.3.7 (45 mg, 0.10 mmol) and R17 (19 μL, 0.20 mmol) in DMF (1.5 mL)potassium carbonate (42 mg, 0.30 mmol) is added. The reaction mixture isheated to 80° C. for 12 h. The mixture is purified directly by reversedphase HPLC. Yield 65%, m/z 526 [M+H]+, rt 0.71 min, LC-MS MethodX018_S01.

The following intermediates as shown in Table 11 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 11 m/z rt LC-MS Intermediate educt Structure of Intermediate [M +H]+ (min) method I-2.3.7.3  I-2.3.7

496 0.77 X018_S01 I-2.3.7.4  I-2.3.7

538 0.72 X018_S01 I-2.3.7.5  I-2.3.7

552 0.79 X018_S01 I-2.3.7.6  I-2.3.7

512 0.72 X018_S01 I-2.3.7.7  I-2.3.7

438 [M + H − BOC]+ 1,11 X018_S01 I-2.3.7.8  I-2.3.7

593 0.69 X018_S01 I-2.3.7.9  I-2.3.7

566 0.79 X018_S01 I-2.3.7.10 I-2.3.7

526 0.75 X018_S01 I-2.3.7.11 I-2.3.7

494 (M + H − BOC)+ 1.03 Z018_S04

The reaction conditions for I-2.3.7.11 differ: Pyridine anddichlormethane instead of potassium carbonate and DMF is used.

Intermediate I-2.3.7.4 is separated according to method chiral SFC B togive the following intermediates as shown in Table 11.1

TABLE 11.1 m/z rt Intermediate Educt Structure of Intermediate [M + H]+(min) LC-MS method I-2.3.7.4.1 I-2.3.7.4

n.d. 3.90 I_OJH_10_IPROP_DEA.M I-2.3.7.4.2 I-2.3.7.4

n.d. 3.4  I_OJH_10_IPROP_DEA.M

Step 4: Synthesis of Example 2

To I-2.3 (2.35 g, 4.4 mmol) in acetonitrile (50 mL) sodium iodide (1.98g, 13 mmol) and chlorotrimethylsilane (1.44 g, 13 mmol) are added. Themixture is stirred for 1 h, then methanol is added, stirred foradditional 30 min and then concentrated. The residue is purified byreversed phase HPLC. Yield 47%, m/z 433 [M+H]+, rt 0.59 min, LC-MSMethod X011_S01.

Method A2.1 Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxo-3H-isobenzofuran-5-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 3

Step 1: Synthesis of Intermediate I-3.1

To I-2.1 (1.00 g, 2.1 mmol) in dioxane (5 mL) R3 (0.58 g, 2.3 mmol) isadded. The mixture is purged with argon.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complexwith dichloromethane (34 mg, 0.04 mmol) and potassium acetate (0.39 g,3.9 mmol) are added. The mixture is heated to 100° C. for 12 h. Water isadded to the reaction mixture, which is extracted with diethyl ether.The organic layer is washed with brine, dried over MgSO₄, filtrated andconcentrated. Yield 74% m/z 532 [M+H]+

The following intermediates as shown in Table 12a are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 12a m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-3.1.1 (1RS)- I-2.2

514 0.90 V011_S01 I-3.1.2 I-2.2

432 1.05 V018_S01 I-3.1.3 I-2.2

514 0.95 Z011_S03 I-3.1.5 I-2.1

450 (Boronacid) 0.67 V011_S01

During the synthesis of intermediate I-3.1.2, I-3.1.4 and I-3.1.5instead of R3 5,5,5′,5′-Tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] isused.

During the synthesis of intermediate I-3.1 I-3.1.2 and I-3.1.4 also thecorresponding boronic acid is isolated as shown in Table 12b. Either theboronic ester or boronic acid is used for the next steps.

TABLE 12b m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-3.1.4 I-2.2.3

432 0.88 V011_S01 I-3.1.6 I-2.1

449 0.42 X016_S01 I-3.1.7 I-2.2

432 0.56 X018_S01

Step 2: Synthesis of Intermediate I-3.2

To I-3.1 (295 mg, 0.66 mmol, as boronic acid (I-3.1.6)) in acetonitrile(4 mL) aq. Na₂CO₃-solution (2 M, 663 μL) is added. The mixture is purgedwith argon, R8 (154 mg, 0.72 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complex with dichloromethane (80mg, 0.10 mmol) are added. The reaction is stirred at 70° C. for 4 h.Ethyl acetate is added and the mixture is filtrated. The filtrate iswashed with water and aq. Na₂CO₃ solution (10%). The organic layer isdried over MgSO₄ and concentrated. The residue is purified by flashchromatography (DCM/methanol=97/3). Yield 53%.

The following intermediates as shown in Table 13 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 13 Inter- m/z rt LC-MS mediate Educt Structure of Intermediate[M + H]+ (min) method I-3.2.1 I-3.1

551 1.08 V011_S01 I-3.2.2 I-3.1.1

520 1.21 V011_S01 I-3.2.5 I-3.1

n.d. n.d. n.d. I-3.2.6 (1S)-I-3.1.1

447/ 491/ 547  1.18 V011_S01 I-3.2.8 I-3.1

n.d. n.d. n.d. I-3.2.10 (1S)-I-3.1.1

519 1.11 V011_S01 I-3.2.11 I-3.1.1

n.d. n.d. n.d. I-3.2.12 I-3.1.1

n.d. n.d. n.d. I-3.2.13 I-3.1.1

n.d. n.d. n.d. I-3.2.15 I-3.1

n.d. n.d. n.d. I-3.2.16 I-3.1

n.d. n.d. n.d. I-3.2.17 I-3.1

n.d. n.d. n.d. I-3.2.36 I-3.1.3

368 (M + H − BOC)+ 0.73 004_CA05 I-3.2.37 I-3.1.3

382 (M + H − BOC)+ 0.75 004_CA05 I-3.2.38 I-3.1.3

415 (M + H − BOC)+ 0.95 004_CA05 I-3.2.39 I-3.1.3

430 (M + H − BOC)+ 0.91 004_CA05 I-3.2.40 I-3.1.3

405 (M + H − BOC)+ 0.74 004_CA05 I-3.2.41 I-3.1.3

405 (M + H − BOC)+ 0.67 004_CA05 I-3.2.42 I-3.1.3

405 (M + H − BOC)+ 0.77 004_CA05 I-3.2.43 I-3.1.3

382 (M + H − BOC)+ 0.72 004_CA05 I-3.2.44 I-3.1.3

394 (M + H − BOC)+ 0.70 004_CA05 I-3.2.45 I-3.1.3

411 (M + H − BOC)+ 0.88 004_CA05 I-3.2.46 I-3.1.3

397 (M + H − BOC)+ 0.68 004_CA05 I-3.2.47 I-3.1.3

379 (M + H − BOC)+ 0.85 004_CA05 I-3.2.48 I-3.1.3

442 (M + H − BOC)+ 0.92 004_CA05 I-3.2.49 I-3.1.3

442 (M + H − BOC)+ 0.94 004_CA05 I-3.2.50 I-3.1.3

412 (M + H − BOC)+ 0.84 004_CA05 I-3.2.51 I-3.1.3

611 n.d. n.d. I-3.2.52 I-3.1.3

613 1.24 V012_S01 I-3.2.53 I-3.1.3

466 (M + H − BOC)+ 0.91 Z018_S04 I-3.2.54 I-3.1.3

647 n.d. n.d. I-3.2.55 I-3.1.2

568 1.23 V011_S01 I-3.2.56 I-3.1.2

622 1.24 V011_S01 I-3.2.57 I-3.1.2

547 0.76 X011_S03 I-3.2.58 I-3.1.2

494 0.57 X011_S03 I-3.2.59 I-3.1.2

494 0.56 X011_S03 I-3.2.60 I-3.1.2

552 0.58 X011_S03 I-3.2.61 I-3.1.2

380 (M + H − BOC)+ 0.52 X011_S03 I-3.2.62 I-3.1.2

380 (M + H − BOC)+ 0.52 X011_S03 I-3.2.63 I-3.1.3

445 (M + H − BOC)+ 0.93 Z018_S04 I-3.2.64 I-3.1.3

538 0.94 Z018_S04 I-3.2.65 I-3.1.3

466 (M + H − BOC)+ 0.91 Z018_S04 I-3.2.66 I-3.1.3

525 (M + H − BOC)+ 0.93 Z011_S03 I-3.2.67 I-3.1.7

538 0.83 X018_S01 I-3.2.68 I-3.1.7

526 1.11 V011_S01 I-3.2.69 I-3.1.7

586 1.29 V011_S01 I-3.2.70 I-3.1.7

640 1.31 V011_S01 I-3.2.71 I-3.1.7

604 n.d. n.d. I-3.2.72 I-3.1.7

n.d. n.d. n.d. I-3.2.73 I-3.1.7

590 1.03 Z011_S03 I-3.2.74 I-3.1

529 0.48 X012_S02 I-3.2.75 I-3.1

543 1.04 V011_S01 I-3.2.76 I-3.1

543 1.02 V011_S01 I-3.2.77 I-3.1.4

n.d. n.d. n.d. I-3.2.78 I-3.1

n.d. n.d. n.d. I-3.2.79 I-3.1.7

539 1.18 V011_S01 I-3.2.80 I-3.1.7

546 (M + H − Boc- t-Bu) 1.106 Z020_S01 I-3.2.81 I-3.1.6

557 1.05 V011_S01 I-3.2.82 I-3.1.6

577 0.50 X018_S02 I-3.2.83 I-3.1.1

644 0.53 X012_S01 I-3.2.84 I-3.1.7

640 0.53 X012_S01 I-3.2.85 I-3.1.7

551 0.59 X011_S03 I-3.2.86 I-3.1.7

544 0.60 X012_S02 I-3.2.87 I-3.1.7

n.d. n.d. n.d. I-3.2.88 I-3.1.2

533 1.08 V011_S01 I-3.2.90 I-3.1.6

563 1.29 V011_S01 I-3.2.91 I-3.1.7

n.d. n.d. n.d.

Intermediate I-3.2.64 is separated according to method chiral SFC A togive the following intermediates as shown in Table 13.1

TABLE 13.1 m/z rt Intermediate Educt Structure [M + H]+ (min) LC-MSmethod I-3.2.64.1 I- 3.2.64

n.d. 3.828 I_ADH_15_MEOH_DEA.M I-3.2.64.2 I- 3.2.64

n.d. 4.631 I_ADH_15_MEOH_DEA.M

Intermediate I-3.2.74, I-3.2.75, I-3.2.81, I-3.2.82, I-3.2.89, I-3.2.90,I-3.2.113, is further processed via hydrogenation before the BOC groupis removed (step 4)

To I-3.2.74 (210 mg, 0.33 mmol) in methanol (10 mL) Pd/C (10%, 90 mg) isadded. The reaction mixture is stirred at 50° C. under hydrogen (50 psi)for 6 h. Then the mixture is filtered and concentrated. The crudeproduct is carried on with step 4. Yield 85%, m/z 531 [M+H]+, rt 0.48min, LC-MS Method X012_S02.

In analogy the following intermediates as shown in Table 17 areprepared.

TABLE 17 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-3.2.122 I- 3.2.75

545 0.98 V011_S01 I-3.2.123 I- 3.2.75

545 1.03 V011_S01 I-3.2.124 I- 3.2.81

559 0.62 X011_S03 I-3.2.125 I- 3.2.82

489 0.44 X018_S02 I-3.2.126 I- 3.2.89

516 1.02 V011_S01 I-3.2.127 I- 3.2.90

475 0.41 X018_S02 I-3.2.128 I-  3.2.113

530 1.12 V011_S01 I-3.2.129 I-  3.2.113

530 1.00 V011_S01

Intermediate I-3.2.91 is further processed in the following way:

To I-3.2.91 (200 mg, 0.28 mmol) in ACN (3 mL) is added p-toluenesulfonic acid monohydrate (79.67 mg, 0.42 mmol) and stirred at r.t. for2.5 h. The reaction mixture is diluted with TEA, filtered and purifiedby reversed phase HPLC.

Yield 68%

Intermediate I-3.2.125, I-3.2.126, I-3.2.129 and I-3.2.131 is furtherprocessed via reductive amination before the BOC group is removed (step4)

To I-3.2.125 (130 mg, 0.266 mmol) in dichlormethane is added3-oxotetrahydrofuran (27.49 mg, 0.319 mmol) and glacial acetic acid(15.22 μL, 0.266 mmol) and stirred for 45 min at r.t. Sodiumtriacetoxyborohydride (83.1 mg, 0.372 mmol) is added and the reactionmixture is stirred at r.t. overnight.

The reaction mixture is diluted with dichlormethane and sat. NaHCO₃. Theorganic layer is separated, dried and concentrated. The crude product isused for the next step without further purification.

Yield 99%, m/z 559 [M+H]+, rt 0.44 min, LC-MS Method X018_S02.

In analogy the following intermediates as shown in Table 18 areprepared.

TABLE 18 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method  I-3.2.133,  I-3.2.126,

586 0.50 X012_S02 I-3.2.134 I-3.2.126

530 1.14 V011_S01 I-3.2.135 I-3.2.129

586 1.09 V011_S01 I-3.2.136 I-3.2.131

n.d. n.d. n.d.

The reaction time for I-3.2.133 and I-3.2.135 is 30 min at r.t. and forI-3.2.134 2 h at r.t. and for I-3.2.136 1 h at r.t.

Intermediate I-3.2.136 is deprotected (see example 359) and furtherprocesses via hydrogenation to give example 358:

To example 359 (20 mg, 0.047 mmol) in methanol (3 mL) Pd/C (10%, 5 mg)is added. The reaction mixture is stirred at r.t. under hydrogen (50psi) for 10 min. Then the mixture is filtered and concentrated. Thecrude product is purified by reversed phase HPLC to give example 358.Yield 35%, m/z 425 [M+H]+, rt 0.715 min, LC-MS Method Z012_S04.

Intermediate I-3.2.127 is further processed via alkylation before theBOC group is removed (step 4)

To I-3.2.127 (71 mg, 0.15 mmol) in DMF (2 mL) is added 2-bromoethylmethyl ether (29.53 μL, 0.31 mmol) and potassium carbonate (41.36, 0.266mmol) and stirred overnight at r.t. The reaction mixture is diluted withdichlormethane and water. The organic layer is separated, dried andconcentrated. The crude product is purified by reversed phase HPLC.Yield 40%, m/z 533 [M+H]+, rt 1.05 min, LC-MS Method V011_S01.

Step 3: Synthesis of Intermediate I-3.3

To I-3.2 (187 mg, 0.35 mmol) in DCM (12 mL) R2 (182 mg, 0.77 mmol) isadded. The reaction mixture is stirred for 12 h, concentrated, dissolvedin ethyl acetate and extracted with 0.1M HCl and water. The organiclayer is dried over MgSO₄ and concentrated. Yield 86%.

The following intermediates as shown in Table 19 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 19 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-3.3.1  I-3.2.1 

533 1.21 V011_S01 I-3.3.3  I-3.2.5 

n.d. n.d. n.d. I-3.3.4  I-3.2.8 

n.d. n.d. n.d. I-3.3.5  I-3.2.15

626 n.d. n.d. I-3.3.6  I-3.2.16

n.d. n.d. n.d. I-3.3.7  I-3.2.17

n.d. n.d. n.d. I-3.3.8  I- 3.2.130

513 0.55 V011_S02 I-3.3.9  I-3.2.75

525 1.17 V011_S01 I-3.3.10 I-3.2.76

525 1.15 V011_S01 I-3.3.11 I- 3.2.122

527 1.15 V011_S01 I-3.3.12 I- 3.2.123

527 1.12 V011_S01 I-3.3.13 I-3.2.78

496 0.54 X012_S02 I-3.3.14 I- 3.2.124

541 0.71 X011-S03 I-3.3.15; I- 3.2.132

541 0.49 X018_S02 I-3.3.16 I- 3.2.133

568 1.22 V011_S01 I-3.3.17 I- 3.2.134

512 1.26 V011_S01 I-3.3.18 I- 3.2.137

515 1.17 V011_S01 I-3.3.19 I- 3.2.128

512 1.25 V011_S01 I-3.3.20 I- 3.2.135

568 1.23 V011_S01

Step 4: Synthesis of Example 3

To I-3.3 (155 mg, 0.30 mmol) in acetonitrile, sodium iodide (134 mg,0.89 mmol) and chlorotrimethylsilane (114 μl, 0.89 mmol) are added. Themixture is stirred for 2 h, then methanol is added, stirred foradditional 30 min and then concentrated. The residue is purified byreversed phase HPLC. Yield 62%, m/z 420 [M+H]+, rt 0.41 min, LC-MSMethod X016_S01.

Method A2.2 Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(4-phenylpiperazin-1-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide

Example 32 Step 1: Synthesis of Intermediate I-3.2.4

To I-3.1.2 (150 mg, 0.30 mmol) in DCM (6 mL), triethylamine (85 μL, 0.61mmol), R112 (55.22 is mg, 0.34 mmol) and copper(II)acetate (85 mg, 0.47mmol) are added. The mixture is stirred for 72 h at r.t. 7M ammoniumsolution in methanol is added, the mixture is concentrated. The residuedissolved in acetonitrile and filtrated. The product is purified byreversed phase HPLC. Yield 54%, m/z 548 [M+H]+, rt 1.37 min, LC-MSMethod V011_S01.

The following intermediates as shown in Table 14 are synthesized in asimilar fashion from the appropriate intermediate

TABLE 14 m/z LC-MS Intermediate Educt Structure of Intermediates [M +H]+ rt (min) method I-3.2.7 I-3.1.2

528 1.10 V011_S01 I-3.2.9 I-3.1.2

550 1.11 V011_S01 I-3.2.14 I-3.1.2

556 1.20 V011_S01 I-3.2.19 I-3.1.2

544 1.22 V011_S01 I-3.2.20 I-3.1.2

354 (M + H − BOC)+ 1.20 V011_S01 I-3.2.22 I-3.1.2

530 1.13 V011_S01 I-3.2.24 I-3.1.2

512 1.28 V011_S01 I-3.2.25 I-3.1.2

500 1.21 V011_S01 I-3.2.26 (forms together with I-3.2.27) I-3.1.2

516 1.02 V011_S01 I-3.2.27 (forms together with I-3.2.26) I-3.1.2

516 1.02 V011_S01 I-3.2.28; I-3.1.2

558 1.25 V011_S01 I-3.2.29 I-3.1.2

500 1.21 V011_S01 I-3.2.30 I-3.1.2

556 1.13 V011_S01 I-3.2.31 I-3.1.2

499 1.49 V011_S01 I-3.2.32; I-3.1.2

514 1.21 V011_S01 I-3.2.33 I-3.1.2

471 1.39 V011_S01 I-3.2.34 I-3.1.2

472 1.36 V011_S01 I-3.2.35 I-3.1.2

473 1.17 V011_S011 I-3.2.92 I-3.1.2

n.d. 0.67 X011_S03 I-3.2.93; I-3.1.2

540 1.09 V011_S01 I-3.2.94 I-3.1.2

561 1.07 V011_S01 I-3.2.95 I-3.1.2

559 1.08 V011_S01 I-3.2.96 I-3.1.2

528 0.78 X011_S03 I-3.2.97 I-3.1.2

528 0.77 X011_S03 I-3.2.98 I-3.1.7

542 1.26 V011_S01 I-3.2.99 I-3.1.7

512 1.26 V011_S01 I-3.2.100 I-3.1.7

526 0.72 X011_S03 I-3.2.101 I-3.1.7

500 1.24 V011_S01 I-3.2.102 I-3.1.4

486 1.13 V011_S01 I-3.2.103 I-3.1.2

584 1.36 V011_S01 I-3.2.104 I-3.1.7

512 1.31 V011_S01 I-3.2.105 I-3.1.7

568 0.75 X011_S03 I-3.2.106 I-3.1.7

498 1.20 V011_S01 I-3.2.107 I-3.1.7

542 1.13 V011_S01 I-3.2.108 I-3.1.7

512 1.29 V011_S01 I-3.2.109 I-3.1.2

572 1.36 V011_S01 I-3.2.110 I-3.1.2

556 0.65 X011_S03 I-3.2.111 I-3.1.1

528 0.79 X011_S03 I-3.2.112 I-3.1.7

513 0.69 X011_S03 I-3.2.114 I-3.1.7

n.d. n.d. n.d. I-3.2.115 I-3.1.7

542 0.99 Z011_S03 I-3.2.116 I-3.1.7

542 1.017 Z011_S03

For the synthesis of the intermediates I-3.2.117 and I-3.2.118 to theeduct I-3.1.2 with the appropriate amine in MeOH 0.14 eq copper(I)oxideis added (as shown in Table 15).

TABLE 15 m/z rt Intermediate Educt Structure of Intermediate [M + H]+(min) LC-MS method I-3.2.117 I-3.1.2 

422 (M + H − BOC)+ 1.32 V011_S01 I-3.2.118 I-3.1.2 

526 1.28 V011_S01 I-3.2.119 I-3.2.118

498 1.84 I_OJH_10_MEOH_DEA.M I-3.2.120 I-3.2.119

525 1.10. V011_S01

The synthesis of I-3.2.119 proceeds in the following way: I-3.2.118 (785mg, 1.49 mmol) is dissolved in THF. LiOH (1.5 eq.) as aq. solution isadded and stirred at r.t. for 9 h. The product mixture is acidified with1 M HCl to pH 5 and purified by HPLC-MS. Yield: 61%.

The amide coupling for synthesis of intermediate I-3.2.120 proceeds inthe following way: I-3.2.119 (40 mg, 0.08 mmol) HATU (33.6 mg, 0.088mmol) and DIPEA (55.3 μL, 0.322 mmol) are dissolved in DMF. The mixtureis stirred at r.t. for 15 min. Dimethylamine (120.6 μL, 0.241 mmol) isadded, and the reaction mixture is stirred at r.t. for 1.5 h. Theproduct mixture is separated to by HPLC-MS.

The fractions are combined and freeze-dried. Yield: 85%.

The following intermediate as shown in Table 16 is synthesized in asimilar fashion from the appropriate intermediate

TABLE 16 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-3.2.121 I-3.2.119

567 1.10 V011_S01

The reaction conditions for I-3.2.94 and I-3.2.95 differ: Pyridineinstead of TEA is used.

The reaction conditions are 80° C. overnight.

The reaction conditions for I-3.2.111 differ: 2 eq of N-MethylmorpholineN-Oxid is added to the reaction.

Step 2: Synthesis of Example 32

To I-3.2.4 (82 mg, 0.15 mmol) in acetonitrile, p-toluenesulfonic acidmonohydrate (95 mg, 0.50 mmol) is added and stirred overnight at r.t.The reaction mixture is basified with ammonium solution. 0.5 mL waterand 1 mL ACN are added. The precipitate is filtered off, washed with ACNand dried. The crude product is triturated with aq. sodiumhydrogencarbonate solution, filtered by suction and dried. Yield 31%,m/z 448 [M+H]+, rt 1.28 min, LC-MS Method V011_S01.

Method A3 Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methylsulfonylphenyl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 4

Step 1: Synthesis of Intermediate I-4.1

To I-1.1 (5.00 g, 14 mmol) in acetonitrile (250 mL) p-toluenesulfonicacid monohydrate (3.05 g, 16 mmol) is added and the mixture is stirredfor 3 d. The precipitate is filtered off and the solution is washed withacetonitrile. The residue is stirred with aq. NaHCO3 solution (2%), andextracted with ethyl acetate. The organic layer is dried over MgSO₄ andconcentrated. Yield 78%, m/z 243/245 [M+H]+, rt 0.76 min, LC-MS MethodV018_S01.

The further intermediates belong to the following description

Synthesis of 2-amino-3-(4-bromo-2-fluoro-phenyl)propanenitrile

Step 1.1: Synthesis of Intermediate I-4.0 (Compare with Synthesis ofIntermediate I-7.1)

To R19 (28.1 g, 104 mmol) and R20 (21.0 g, 95 mmol) in DCM (130 mL)benzyltrimethyl-ammonium chloride (1.77 g, 9.5 mmol) is added. Understrong stirring water (8 mL) and aq. NaOH solution (19 mol/L, 9 mL) areadded (exothermic reaction). The reaction mixture is stirred for 12 h.Water is added and the product is extracted with DCM. The organic layeris dried over MgSO₄ and concentrated. The crude product is used in step2. Yield>95%, rt 1.56 min, LC-MS Method V003_(—)003.

The following intermediates as shown in Table 20 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 20 m/z rt Intermediate Structure of Intermediate [M + H]+ (min)LC-MS method I-4.0.1

n.d. n.d. n.d. I-4.0.2

425/427 1.51 V011_S01 I-4.0.3

n.d. n.d. n.d. I-4.0.4

495/497 0.96 X018_S01Step 1.2: Synthesis of Intermediate I-4.1.1 (Compare with Synthesis ofIntermediate I-7.2)

To I-4.0 (40.8 g, 100 mmol) in dioxane (400 mL) hydrogen chloridesolution in dioxane (4 mol/L, 27.5 mL, 9.5 mmol) is added. The reactionmixture is stirred for 12 h. Aq. hydrochloric acid (1 mol/L, 100 mL) isadded and the mixture is stirred for additional 2 h. The reaction isconcentrated, the residue is stirred with acetonitrile and theprecipitate is filtered off. Yield 49%, m/z 243 [M+H]+, rt 0.42 min,LC-MS Method X001_(—)004.

The following intermediates as shown in Table 21 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 21 m/z rt Intermediate educt Structure [M + H]+ (min) LC-MS methodI-4.1.1.1 I-4.0.1

261 0.35 Z001_002 I-4.1.1.2 I-4.0.2

261/263 0.34 V012_S01 I-4.1.1.3 I-4.0.3

259 0.39 X001_004 I-4.1.1.4 I-4.0.4

331/333 0.48 V018_S01

Step 2: Synthesis of Intermediate I-2.2

To R5 (2.82 g, 11 mmol) in dry DCM (150 mL) diisopropylethylamine (5.8mL, 33 mmol) and HATU (5.1 g, 13 mmol) are added and the mixture isstirred for 30 min. Then a solution of I-4.1 (2.75 g, 11 mmol) in DCM(50 mL) is added and stirred for 12 h. The mixture is washed with water,aq. K2CO3 solution (5%) and 1 M HCl. The organic layer is dried overMgSO₄ and concentrated. Yield 68%, m/z 466/468 [M+H]+, rt 1.25 min,LC-MS Method V011_S01.

The following intermediates as shown in Table 22 are synthesized in asimilar fashion from the appropriate intermediate: ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group)

TABLE 22 Intermediate educt Structure m/z [M + H]+ rt (min) LC-MS methodI-4.2.1 I-4.1.1  

466 0.78 X001_004 I-4.2.2 I-4.1.1.1

484 1.29 V011_S01 I-4.2.3 I-4.1.1.2

484/486 1.29 V011_S01 I-4.2.4 I-4.1.1.3

n.d. n.d. n.d. I-4.2.5 I.4.1.1.4

554 1.42 V011_S01

Step 3: Synthesis of Intermediate I-4.3

To I-2.2 (300 mg, 0.64 mmol) in acetonitrile (7.5 mL) R9 (142 mg, 0.71mmol) is added. The mixture is purged with argon1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (42 mg,0.10 mmol) and aq. sodium carbonate solution (2 mol/L, 0.64 mL) areadded and heated to 70° C. for 2.5 h. Ethyl acetate and water are addedto the reaction mixture. The organic layer is washed with aq. NaHCO3solution (5%) and water. The organic layer is dried over MgSO₄ andconcentrated. Yield raw product>95% m/z 442 [M+H]+, rt 0.93 min, LC-MSMethod Z018_S04.

The following intermediates as shown in Table 23 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 23 Intermediate Educt Structure of Intermediate m/z [M + H]+ rt(min) LC-MS method I-4.3.1  I-4.2.1 

567 1.19 V011_S01 I-4.3.2  I-4.2.1 

533 0.75 X001_004 I-4.3.3  I-2.2  

442 0.92 Z018_S04 I-4.3.4  I-4.2.3 

585 1.20 V011_S01 I-4.3.5  I-4.2.1 

519 0.62 Z001_002 I-4.3.6  1-2.2  

429 0.95 Z018_S04 I-4.3.8  I-4.2.2 

551 1.22 V011_S01 I-4.3.9  I-4.2.1 

n.d. 1.39 V003_003 I-4.3.10 I-4.2.1 

543 0.57 001_CA07 I-4.3.11 I-4.2.1 

518 0.55 001_CA07 I-4.3.12 I-4.2.1 

n.d. n.d. n.d. I-4.3.13 I-4.2.1 

532 0.57 001_CA07 I-4.3.14 I-4.2.1 

556 0.60 001_CA07 I-4.3.15 I-4.2.3 

551 1.21 V011_S01 I-4.3.16 I-4.2.1 

506 0.56 001_CA07 I-4.3.17 I-4.2.1 

541 0.60 001_CA07 I-4.3.18 I-4.2.1 

542 0.56 001_CA07 I-4.3.19 1-4.2.5 

621 1.33 V011_S01 I-4.3.20 I-4.2.1 

556 0.60 001_CA07 I.4.3.21 I-4.2.1 

556 0.62 001_CA07 I-4.3.22 I-4.2.1 

532 0.58 001_CA07 I-4.3.23 I-4.2.1 

n.d. 1.22 Z018_S04 I-4.3.24 I-4.2.4 

n.d. n.d. n.d. I-4.3.25 I-4.2.1 

506 0.55 001_CA07 I-4.3.26 I-4.2.1 

n.d. n.d. n.d. I-4.3.27 I-4.2.1 

534 0.63 001_CA07 I-4.3.28 I-2.2  

500 0.98 V011_S01 I-4.3.29 I-2.2  

442 (M + H − BOC)+ 1.09 Z018_S04 I-4.3.30 I-4.3.29

414 (M + H − BOC)+ 0.60 Z011_S03 I-4.3.31 I-2.2  

408 (M + H − BOC)+ 0.93 Z018_S04

The reaction conditions for I-4.3.28 differ: Under argon atmosphereI-2.2 (250 mg, 0.54 mmol), potassium carbonate (150 mg, 1.07 mmol),copper (I) iodide (10 mg, 0.05 mmol), N,N′-dimethylethylendiamine (25μL, 0.23 mmol) and 4-methyl-piperazin-2-one (75 mg, 0.66 mmol) indioxane (10 mL) are heated to 80° C. for 8 d. The reaction mixture isfiltered and the solution is concentrated. The residue is purified byreversed phase HPLC. Yield 30%, m/z 500 [M+H]+, rt 0.98 min, LC-MSMethod V011_S01.

The synthesis of I-4.3.30 proceeds in the following way: I-4.3.29 (509mg, 0.94 mmol) is dissolved in dioxane. LiOH (1.5 eq.) as aq. solutionis added dropwise to the solution and stirred at r.t. for 8 h. Theproduct mixture is extracted 2× with DCM. The organic layer is extractedtwice with water. The water phase is acidified with 1 M HCl to pH 4, thesolvent removed in vacuo to yield the crude product, which is purifiedby HPLC-MS (Gilson, mass flow 120 mL/min, 10 μM, 200 g Xbridge RP18,ACN/water/NH₃). Yield: 44%.

Intermediate I-4.3.19 is additionally treated with BBr₃ to give example120:

I-4.3.19 (600 mg, 0.97 mmol) in DCM (50 mL) is stirred at −5° C. Thenboron tribromide solution (1 mol/L in DCM, 2.90 mL) is added dropwise.The reaction mixture is stirred at 0° C. for 90 min and then stirred atroom temperature for additional 12 h. The mixture is cooled down againto −5° C. and is quenched with conc. ammonia solution. The mixture isconcentrated and purified by reversed phase HPLC. Yield 5%, m/z 429[M+H]+, rt 0.81 min, LC-MS Method V018_S04.

Additional Step: Amide Coupling to Afford I-4.3.32

The amide coupling for synthesis of intermediate I-4.3.32 proceeds inthe following way: I-4.3.30 (35 mg, 0.068 mmol) TBTU (45 mg, 0.14 mmol)and N-methylmorpholine (75 μL, 0.68 mmol) are is dissolved in DMF. Themixture is stirred at r.t. for 5 min. 0.5 M ammonia in dioxane (2 mL, 1mmol) is added, and the reaction mixture is stirred at r.t. for 12 h.The product mixture is separated by HPLC-MS (Waters, 30×100 mm, 10 μM,sunfire RP18, ACN/water/TFA). The fractions are combined andfreeze-dried. Yield: 59%.

The following amide intermediates as shown in Table 24.1 are synthesizedin a similar fashion from the appropriate intermediates:

TABLE 24.1 m/z rt LC-MS Intermediate Educt Structure of Intermediate[M + H]+ (min) method I-4.3.32 I-4.3.30

413 (M + H − BOC)+ 0.89 Z018_S04 I-4.3.33 I-4.3.30

427 (M + H − BOC)+ 0.92 Z018_S04 I-4.3.34 I-4.3.30

455 (M + H − BOC)+ 1.00 Z018_S04 I-4.3.35 I-4.3.30

467 (M + H − BOC)+ 0.99 Z018_S04 I-4.3.36 I-4.3.30

441 (M + H − BOC)+ 0.95 Z018_S04 I-4.3.37 I-4.3.31

435 (M + H − BOC)+ 0.95 Z018_S04 I-4.3.38 I-4.3.31

490 (M + H − BOC)+ 0.75 Z018_S04 I-4.3.39 I-4.3.31

421 (M + H − BOC)+ 0.91 Z018_S04 I-4.3.40 I-4.3.31

491 (M + H − BOC)+ 0.94 Z018_S04 I-4.3.41 I-4.3.31

477 (M + H − BOC)+ 0.93 Z018_S04 I-4.3.42 I-4.3.31

475 (M + H − BOC)+ 1.02 Z018_S04 I-4.3.43 I-4.3.31

435 (M + H − BOC)+ 0.94 Z018_S04 I-4.3.44 I-4.3.31

461 (M + H − BOC)+ 0.97 Z018_S04 I-4.3.45 I-4.3.30

496 (M + H − BOC)+ 0.89 Z011_S03 I-4.3.46 I-4.3.30

519 (M + H − BOC)+ 0.90 Z018_S04 I-4.3.47 I-4.3.30

524 (M + H − BOC)+ 0.97 Z011_S03 I-4.3.48 I-4.3.30

540 (M + H − BOC)+ 0.91 Z011_S03 I-4.3.49 I-4.3.30

422 (M + H − BOC)+ 0.98 Z011_S03 I-4.3.50 I-4.3.30

483 (M + H − BOC)+ 0.90 Z011_S03 I-4.3.51 I-4.3.30

424 (M + H − BOC)+ 0.86 Z011_S03 I-4.3.52 I-4.3.30

564 (M + H − BOC)+ 0.98 Z018_S04 I-4.3.53 I-4.3.30

510 (M + H − BOC)+ 0.85 Z011_S03 I-4.3.54 I-4.3.30

583 (M + H − BOC)+ 0.89 Z011_S03 I-4.3.55 I-4.3.30

497 (M + H − BOC)+ 0.91 Z011_S03 I-4.3.56 I-2.3.41

413 (M + H − BOC)+ 0.84 Z011_S03 I-4.3.57 I-2.3.41

519 (M + H − BOC)+ 0.94 Z018_S04 I-4.3.58 I-2.3.80

522 (M + H − BOC)+ 0.87 Z018_S04 I-4.3.59 I-2.3.81

397 (M + H − BOC)+ 0.86 Z018_S04 I-4.3.60 I-2.3.81

503 (M + H − BOC)+ 0.88 Z011_S03 I-4.3.61 I-2.3.81

480 (M + H − BOC)+ 0.74 Z018_S04 I-4.3.62 I-2.3.81

425 (M + H − BOC)+ 0.91 Z018_S04 I-4.3.63 I-2.3.82

407 (M + H − BOC)+ 1.02 Z018_S04 I-4.3.64 I-2.3.82

490 (M + H − BOC)+ 0.76 Z018_S04 I-4.3.65 I-2.3.80

467 (M + H − BOC)+ 0.91 Z018_S04 I-4.3.66 I-2.3.80

480 (M + H − BOC)+ 0.73 Z018_S04

The reaction conditions for I-4.3.63 differ: I-2.3.82 (100 mg, 0.197mmol), HATU (82.4 mg, 0.217 mmol) and DIPEA (68 μL, 2 eq) are dissolvedin DMF. The mixture is stirred at r.t. for 30 min. Ammonium chloride(63.2 mg, 1.182 mmol) and DIPEA (204 μL, 6 eq) are added, and thereaction mixture is stirred at r.t. for 3 h. The product mixture isseparated by HPLC-MS (Waters, 30×100 mm, 10 μM, xBridge RP18,ACN/water/TFA). The fractions are combined and freeze-dried. Yield: 27%.

The reaction conditions for I-4.3.65 and I-4.3.66 differ: DCM is used assolvent instead of DMF.

Step 4: Synthesis of Example 4

I-4.3 (348 mg, 0.64 mmol) in formic acid is stirred for 10 min at 40° C.The reaction solution is diluted with DMF and directly purified byreversed phase HPLC. Yield 86%, m/z 442 [M+H]+, rt is 0.65 min, LC-MSMethod Z018_S04.

Method A4 Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-[4-(1H-indol-5-yl)triazol-1-yl]phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 5

Step 1: Synthesis of Intermediate I-5.1

I-2.1 (2.26 g, 4.7 mmol), sodium azide (0.61 g, 9.3 mmol),trans-(1R,2R)-N,N′-bismethyl-1,2-cylcohexane diamine (147 μl, 0.93mmol), copper(I)iodide (89 mg, 0.47 mmol) and L-ascorbic acid sodiumsalt (92 mg, 0.47 mmol) are dissolved in ethanol/water=7/3 (60 mL). Themixture is heated to 100° C. for 1.5 h. Water and DCM are added to thereaction mixture. The organic layer is washed with water and brine,dried over MgSO₄ and concentrated. The residue is purified by reversedphase HPLC. Yield 85% m/z 447 [M+H]+, rt 0.91 min, LC-MS MethodZ018_S04.

Step 2: Synthesis of Intermediate I-5.2

To I-5.1 (1.76 g, 3.9 mmol) in anhydrous DCM (30 mL) R2 (2.35 g, 9.9mmol) is added. The reaction mixture is stirred for 11 h. The reactionmixture is extracted with 0.5M HCl and water. The organic layer isextracted with half saturated Na2CO3 solution, water and brine. Theresidue is is purified by reversed phase HPLC. Yield 54% m/z 329 [M+H]+,rt 0.96 min, LC-MS Method Z018_S04.

Step 3: Synthesis of Example 5

To R10 (28 mg, 0.20 mmol) in DMSO (1.3 mL) I-5.2 (43 mg, 0.10 mmol) isadded. Then copper(II) sulfate pentahydrate (2.2 mg, 0.011 mmol),L-ascorbic acid sodium salt (11 mg, 0.05 mmol) and 100 μL water areadded. The reaction mixture is stirred for 12 h. The reaction mixture isdiluted with DMF and directly purified by reversed phase HPLC. Theachieved substance is dissolved in formic acid, stirred at 40° C. for 10min and the reaction mixture is purified again by reversed phase HPLC.Yield 34% m/z 470 [M+H]+, rt 0.70 min, LC-MS Method Z018_S04.

Method A5 Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 6

Step 1: Synthesis of Intermediate I-6.1

To I-3.1 (90 mg, 0.20 mmol) in DCM (4 mL), triethylamine (60 μL, 0.43mmol), R11 (23 μL, 0.21 mmol) and copper(II)acetate (55 mg, 0.30 mmol)are added. The mixture is stirred for 12 h. 7M ammonium solution inmethanol is added, the mixture is concentrated. The residue dissolved inacetonitrile and filtrated. The product is purified by reversed phaseHPLC. Yield 32%, m/z 504 [M+H]+, rt 1.00 min, LC-MS Method V011_S01.

The following intermediates as shown in Table 24.2 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 24.2 m/z rt LC-MS Intermediate Educt Structure of Intermediate[M + H]+ (min) method I-3.2.89 I-3.1.5

606 1.40 V011_S01 I-3.2.113 I-3.1.5

606 1.37 V011_S01

Step 2: Synthesis of Intermediate I-6.2

To I-6.1 (40 mg, 0.08 mmol) in DCM (1 mL) R2 (35 mg, 0.15 mmol) isadded. The reaction mixture is stirred for 12 h. The reaction mixture isconcentrated and the residue is purified by to reversed phase HPLC.Yield 67%, m/z 486 [M+H]+, rt 1.12 min, LC-MS Method V011_S01.

Step 3: Synthesis of Example 6

To I-6.2 (25 mg, 0.05 mmol) in acetonitrile, p-toluenesulfonic acidmonohydrate (35 mg, 0.18 mmol) is added and stirred for 12 h. Theproduct is purified by reversed phase HPLC. Yield 86%, is m/z 386[M+H]+, rt 0.98 min, LC-MS Method V011_S01.

Method B Synthesis of(1S,2S,4R)-N-[2-[4-(1-acetyl-5-methyl-pyrazol-3-yl)-2-fluoro-phenyl]-1-cyano-ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 7

Step 1: Synthesis of Intermediate I-7.1

R12 (340 mg, 1.54 mmol), R13 (480 mg, 1.54 mmol),benzyltrimethylammonium chloride (29 mg, 0.15 mmol) and DCM (10 mL) areput together. Under stirring water (250 μL) and sodium hydroxidesolution (19 mol/L, 146 μL) are added. The reaction mixture is stirredfor 1 h. Half saturated brine and DCM are added. The organic layer isconcentrated and purified by reversed phase HPLC. Yield 22%. m/z 451[M+H]+, rt 1.48 min, LC-MS Method V011_S01.

The following intermediate as shown in Table 25 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 25 m/z rt LC-MS Intermediate Structure [M + H]+ (min) methodI-7.1.1

447/449 0.78 X012_S01 I-7.1.2

356 0.75 X012_S01 I-7.1.3

500 0.95 X012_S01 I-7.1.4

413 0.90 X012_S01 I-7.1.5

401 0.86 X012_S01 I-7.1.6

500 0.95 X012_S01 I-7.1.7

466 0.82 X011_S01

Step 2: Synthesis of Intermediate I-7.2

To I-7.1 (155 mg, 0.34 mmol) in dioxane (6 mL) aq. HCl (1 mol/L, 361 μL)is added. The reaction mixture is stirred for 1 h. 135 μL aq. HCl (1 M)is added and stirred for additional 30 min. The product is purified byreversed phase HPLC. Yield>95%. m/z 287 [M+H]+, rt 1.01 min, LC-MSMethod V011_S01.

The following intermediates as shown in Table 26 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 26 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-7.2.1 I-7.1.1

284/286 0.48 X012_S01 I-7.2.2 I-7.1.2

n.d. n.d. n.d. I-7.2.3 I-7.1.3

336 0.56 X012_S01 I-7.2.4 I-7.1.4

249 0.47 X012_S01 I-7.2.5 I-7.1.5

227 0.43 X012_S01 I-7.2.6 I-7.1.6

336 0.55 X012_S01 I-7.2.7 I-7.1.7

318/320 (M + H2O) 0.48 X011_S02

Step 3: Synthesis of Intermediate I-7.3

To R5 (50 mg, 0.21 mmol) in DMF (1.5 mL) HATU (87 mg, 0.23 mmol) anddiisopropylethylamine (143 μL, 0.83 mmol) are added and the reactionmixture is stirred for 15 min. Then intermediate I-7.2 (87 mg, 0.22mmol) is added and the mixture stirred for 12 h. The reaction solutionis purified by reversed phase HPLC. Yield 81%, m/z 510/454/410 [M+H]+,rt 1.28 min, LC-MS Method V011_S01.

The following intermediates as shown in Table 27 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 27 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-7.3.1 I-7.2.1

506/508 0.66 X012_S01 I-7.3.2 I-7.2.2

415 0.61 X012_S01 I-7.3.3 I-7.2.3

559 0.84 X012_S01 I-7.3.4 I-7.2.4

472 0.78 X012_S01 I-7.3.5 I-7.2.5

460 0.74 X012_S01 I-7.3.6 I-7.2.6

559 0.84 X012_S01 I-7.3.7 I-7.2.7

524/526 0.71 X011_S02

Intermediate I-7.3.7 is separated according to method “Chiral SFC F” togive the following compounds of Table 28

TABLE 28 m/z rt SFC Intermediate Educt Structure [M + H]+ (min) methodI-7.3.8 I-7.3.7

n.d. 2.432 I_IC_20_MEOH_NH3. M I-7.3.9 I-7.3.7

n.d. 1.946 I_IC_20_MEOH_NH3. M

Step 4: Synthesis of Example 7

To I-7.3 (40 mg, 0.08 mmol) in acetonitrile (1 mL) sodium iodide (14 mg,0.09 mmol) and chlorotrimethylsilane (12 μL, 0.09 mmol) are added. Themixture is stirred for 20 min. The product is purified by reversed phaseHPLC. Yield 39%, m/z 410 [M+H]+, rt 0.96 min, LC-MS Method V018_S01

For example 58 I-7.3 is stirred in formic acid at 50° C. for 10 min in apressure vessel.

Method C Synthesis of(1S,2S,4R)-N-[1-cyano-2-(1H-indazol-5-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 8

Step 1: Synthesis of Intermediate I-8.1

To R5 (102 mg, 0.42 mmol) in DMF (3 mL) diisopropylethylamine (296 μL,1.70 mmol) and TBTU (136 mg, 0.23 mmol) are added and the reactionmixture is stirred for 15 min. Then R14 (135 mg, 0.42 mmol) is added andthe mixture is stirred for additional 1 h. Water is added to thereaction mixture and extracted with ethyl acetate. The organic layer iswashed with brine, dried over Na2SO4 and concentrated. Yield 70%.

The following intermediate as shown in Table 29 is synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the amide group):

TABLE 29 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) methodI-8.1.1 R14.1

428 0.91 V011_S01 I-8.1.2 R14.2

437 0.64 X012_S01 I-8.1.3 R47  

512 1.26 V011_S01 I-8.1.4 R49  

517 1.09 V011_S01

The reaction conditions for I-8.1.3 and I-8.1.4 differ: HATU is usedinstead of TBTU.

Step 2: Synthesis of Intermediate I-8.2

To I-8.1 (126 mg, 0.29 mmol) in DCM (1 mL) R2 (155 mg, 0.65 mmol) isadded. The reaction mixture is stirred for 12 h and then concentrated.Yield 100% m/z 310/354/410 [M+H]+, rt 1.02 min, LC-MS Method V012_S01.

The following intermediates as shown in Table 30 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 30 m/z LC-MS Intermediate educt Structure [M + H]+ rt (min) methodI-8.2.1 I-8.1.1

n.d n.d n.d I-8.2.2 I-8.1.2

420 0.70 X012_S01 I-8.2.3 I-8.1.3

494 1.37 V011_S01 I-8.2.4 I-8.1.4

499 1.22 V011_S01 I-8.2.5 I-24.3.2

527 0.66 X011_S03

Step 3: Synthesis of Example 8

To I-8.1 (120 mg, 0.29 mmol) in acetonitrile (7 mL) sodium iodide (132mg, 0.88 mmol) and chlorotrimethylsilane (106 μl, 0.88 mmol) are added.The mixture is stirred for 12 h, then methanol (7 mL) is added, stirredfor 1 h and then concentrated. The residue is dissolved in ethylacetate, washed with water and brine, dried over Na₂SO₄ andconcentrated. The product is purified by reversed phase HPLC. Yield 19%,m/z 310 [M+H]+, rt 0.86 min, LC-MS Method V011_S01.

Method D Synthesis of(1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-8-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 9

Step 1: Synthesis of Intermediate I-9.1

I-7.3.1 (200 mg, 0.39 mmol) and R16 (65 mg, 0.47 mmol) in acetonitrile(5 mL) is purged with argon. 1,1-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (26 mg, 0.04 mmol) and aq. sodium carbonatesolution (2 mol/L, 395 μL) are added and heated to 70° C. for 3 h. DCMand water are added to the reaction mixture. The organic layer is driedover MgSO₄ and concentrated. The product is purified by reversed phaseHPLC. Yield 50% m/z 487 [M+H]+, rt 0.60 min, LC-MS Method X012_S01.

Step 2: Synthesis of Example 9

To I-9.4 (115 mg, 0.24 mmol) in acetonitrile (5 mL) sodium iodide (106mg, 0.71 mmol) and chlorotrimethylsilane (90 μL, 0.71 mmol) are added.The mixture is stirred for 90 min. The product is purified by reversedphase HPLC. Yield 32%, m/z 387 [M+H]+, rt 0.39 min, LC-MS MethodX012_S01.

Synthesis of Intermediate I-9.1.1

I-9.1 (100 mg, 0.2 mmol) and MeI (14.2 μL, 0.23 mmol) are dissolved in 2mL DMF, and NaH (9.04 mg, 0.23 mmol, as 60% suspension in paraffin oil)is added. After stirring for 12 h at r.t., the mixture is diluted withmethanol, filtered and purified by HPLC. The product fractions arefreeze-dried to yield 42 mg (41%) I-9.1.1. m/z 501 [M+H]+, rt 0.65 min,LC-MS Method X012_S01.

Boc deprotection to Example 206 is performed in analogy to the synthesisof Example 9.

Method D1 Synthesis of(1S,2S,4R)-N-[2-(3-chloro-5-methyl-6-oxo-phenanthridin-8-yl)-1-cyano-ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 305

Step 1: Synthesis of Intermediate I-18.1

To I-7.3.1 (4.0 g, 7.9 mmol) in anhydrous dioxane (50 mL) R3 (2.93 g,11.5 mmol) and potassium acetate (2.27 g, 23.2 mmol) are added. Themixture is purged with argon,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichlormethan complex (PdCl₂(dppf)) (0.66 g, 0.81 mmol) is added to themixture and heated to 70° C. overnight. The reaction mixture is dilutedwith DCM and water. The organic layer is separated, dried andconcentrated. The residue to is purified by reversed phase HPLC. Yield71% m/z 554 [M+H]+, rt 0.74 min, LC-MS Method X011_S03.

The following intermediates as shown in Table 31 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 31 m/z LC-MS Intermediate educt Structure [M + H]+ rt (min) methodI-18.1.1 I-7.3.7

572 0.72 X011_S02 I-18.1.2 I-7.3.8

572 0.74 X012_S01

Step 2: Synthesis of Intermediate I-18.2

To I-18.1 (150 mg, 0.27 mmol) in anhydrous ACN (5 mL)(5-chloro-2-iodophenyl)methanamine (72.498 mg, 0.27 mmol) is added andpurged with argon. 1,1 bis(di-tert.butylphosphino)ferrocene to palladiumdichloride (17.66 mg, 0.027 mmol) and a solution of sodium carbonate inwater 2 mol/L (0.271 mL, 0.54 mmol) are added, purged again with argonand heated to 70° C. for 6 h. The reaction mixture is diluted with DCMand water. The organic layer is separated, dried and concentrated. Thecrude residue is used for the next step without further purification.Yield 93% m/z 536[M+H]+, rt 0.71 min, LC-MS Method X012_S01.

The following intermediates as shown in Table 32 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 32 m/z rt LC-MS Intermediate Educt Structure [M + H]+ (min) methodI-18.2.1 I-18.1.1

530 0.62 X011_S03 I-18.2.2 I-18.1.1

523 0.66 X011_S02 I-18.2.3 I-18.1

548 0.48 X011_S03 I-18.2.4 I-18.1.1

505 0.65 X011_S02 I-18.2.5 I-18.1.1

523 0.66 X011_S02 I-18.2.6 I-18.1

541 0.69 X012_S02 I-18.2.7 I-18.1

522 0.65 X012_S01 I-18.2.8 I-18.1

512 0.57 X012_S01 I-18.2.9 I-18.1

545 0.61 X011_S03 I-18.2.10 I-18.1

523 0.68 X012_S02 I-18.2.11 I-18.1

555 0.69 X011_S03 I-18.2.12 I-18.1

580 0.60 X011_S03 I-18.2.13 I-18.1

526 0.64 X012_S01 I-18.2.14 I-18.1

521 0.67 X011_S03 I-18.2.15 I-18.1

558 0.50 X012_S01 I-18.2.16 I-18.1

530 0.54 X011_S03 I-18.2.17 I-18.1

505 0.61 X012_S01 I-18.2.18 I-18.1

512 0.45 X012_S01 I-18.2.19 I-18.1

523 0.62 X012_S01 I-18.2.20 I-18.1

545 0.61 X011_S03 I-18.2.21 I-18.1

517 0.61 X011_S03 I-18.2.22 I-18.1

565 0.53 X012_S01 I-18.2.23 I-18.1

602 0.66 X012_S01 I-18.2.24 I-18.1.2

505 0.61 X012_S01 I-18.2.25 I-18.1.2

523 0.63 X012_S01 I-18.2.26 I-18.1.2

541 0.64 X012_S01 I-18.2.27 I-18.1.2

548 0.60 X012_S01 I-18.2.28 I-18.1.2

519 0.67 X012_S01 I-18.2.29 I-18.1

570 0.59 X012_S01

Step 3: Synthesis of Example 305

To I-18.2 (270 mg, 0.25 mmol) in THF (3 mL) methanesulfonic acid (81.87μL, 1.26 mmol) is added and the reaction mixture is stirred at r.t.overnight. The reaction mixture is concentrated and the residue ispurified by reversed phase HPLC. Yield 14% m/z 435 [M+H]+, rt 0.48 min,LC-MS Method X012_S01.

Method E Synthesis of(1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-3-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideand(1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-1-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 123 and 128

Step 1: Synthesis of Intermediate I-10.1

To I-7.3.2 (6.0 g, 14.5 mmol) in ethyl acetate (100 mL) tin(II)chloridedihydrate (16.3 g, 72.4 mmol) is added. The reaction mixture is stirredfor 12 h. The mixture is set basic with potassium carbonate and aq.sodium hydroxide solution. The organic layer is separated, is dried overMgSO₄ and is concentrated. The residue is purified by reversed phaseHPLC. Yield 32% m/z 385 [M+H]+, rt 0.42 min, LC-MS Method X012_S01.

Step 2: Synthesis of Intermediate I-10.2

To R23 (0.70 g, 2.81 mmol) in DCM (20 mL) diisopropylethylamine (1.20mL, 7.02 mmol) and HATU (1.09 g, 2.81 mmol) are added and the reactionmixture is stirred for 7 min. Then intermediate I-10.1 (0.90 g, 2.34mmol) is added and the mixture is stirred for additional 12 h. Themixture is concentrated and the residue is purified by flashchromatography (cyclohexane/ethyl acetate=70/30). Yield 90% m/z 615[M+H]+, rt 0.66 min, LC-MS Method X012_S01.

The following intermediate as shown in Table 33 is synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 33 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) methodI-10.2.1 I-10.1

585/587 0.67 X012_S01

Step 3: Synthesis of Intermediate I-10.3

To I-10.2 (800 mg, 1.30 mmol) in DMF (20 mL) sodium hydride (58 mg, 1.43mmol) is added and the reaction mixture is stirred for 10 min. Then2-(trimethylsilyl)ethoxymethylchloride (0.25 mL, 1.43 mmol) is added andthe mixture is stirred for additional 2 h. Water and DCM is added to themixture and the organic layer is concentrated. The residue is purifiedby reversed phase HPLC. Yield 26% m/z 745 [M+H]+, rt 0.85 min, LC-MSMethod X012_S01.

The following intermediate as shown in Table 34 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 34 m/z rt LC-MS Intermediate Educt Structure [M + H]+ (min) methodI-10.3.1 I-10.2.1

715/717 0.84 X012_S01

Step 4: Synthesis of Intermediate I-10.4

To I-10.3 (200 mg, 0.27 mmol) in anhydrous DMF (10 mL)tetrakis(triphenylphosphine)palladium (16 mg, 0.01 mmol) and sodiumcarbonat (58 mg, 0.55 mmol) is added. The reaction mixture is heated to150° C. for 5 h. Water and ethyl acetate is added to the mixture. Theorganic layer is dried to over MgSO₄ and is concentrated. The residue ispurified by reversed phase HPLC. Yield 34% m/z 617 [M+H]+, rt 0.84 min,LC-MS Method X012_S01.

During this ring cyclization both isomeres are obtained; but it is firstpossible to separated them by reversed phase HPLC on the last step (seestep 6).

The following intermediate as shown in Table 35 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 35 m/z rt LC-MS Intermediate Educt Structure [M + H]+ (min) methodI-10.4.1 I-10.3.1

635 0.86 X012_S01

Step 5: Synthesis of Intermediate I-10.5

To I-10.4 (57 mg, 0.09 mmol) in acetonitrile (5 mL) sodium iodide (42mg, 0.28 mmol) and chlorotrimethylsilane (35 μL, 0.28 mmol) are added.The mixture is stirred for 90 min. Then methanol (5 mL) is added and themixture is stirred for additional 15 min. The mixture is concentratedand DCM and water is added to the residue. The organic layer isseparated, is dried over MgSO₄ and concentrated again. The crude productis carried on with step 6. Yield>95%, m/z 517 [M+H]+, rt 0.62 min, LC-MSMethod X012_S01.

Step 6: Synthesis of Example 123 and 128

I-10.5 (48 mg, 0.09 mmol) is stirred in formic acid for 48 h. Themixture is purified by reversed phase HPLC. It is possible to separatethe both isomers:

Isomer 1=example 123: yield 3%, m/z 387 [M+H]+, rt 0.38 min, LC-MSMethod X012_S01,Isomer 2=example 128: yield 6%, m/z 387 [M+H]+, rt 0.35 min, LC-MSMethod X012_S01.

Method W Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-[(1-methyl-4-piperidyl)oxy]phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 319

Step 1: Synthesis of Intermediate I-19.1

I-2.2 (300 mg, 0.64 mmol) in anhydrous toluene is purged with argon.4-hydroxy-1-methylpiperidine (148.18 mg, 1.29 mmol), allylpalladiumchloride dimer (5.88 mg, 0.016 mmol),2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′-4′-6′-tri-1-propyl-1,1′-biphenyl(18.09 mg, 0.039 mmol), cesium carbonate (314.4 mg, 0.965 mmol) andmolecular sieve (4A) are added and purged with argon again. The reactionmixture is stirred at 90° C. for 21 h. Afterwards filtered through a padof celite, washed with ethyl acetate and concentrated. The crude residueis purified by reversed to phase HPLC and freeze dried. Yield 16%.

Step 2: Synthesis of Example 319 (See Method A2, Step 4)

To I-19.1 (50 mg, 0.1 mmol) in acetonitrile (6 mL) sodium iodide (45 mg,0.3 mmol) and chlorotrimethylsilane (38.1 μL, 0.3 mmol) are added. Themixture is stirred for 2 h, then methanol is added, stirred foradditional 30 min and then concentrated. The residue is purified byreversed phase HPLC. Yield 34%, m/z 401 [M+H]+, rt 0.31 min, LC-MSMethod X012_S02.

Method W1 Synthesis of(1S,2S,4R)-N-[(1S)-1-cyano-2-[4-[3-(dimethylamino)-1-piperidyl]-2-fluoro-phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 344

Step 1: Synthesis of Intermediate I-20.1

To I-2.2 (300 mg, 0.64 mmol) in anhydrous dioxane (8 mL) are added3-dimethylamino-piperidine (164.96 mg, 1.29 mmol) and cesium carbonate(846.87 mg, 2.57 mmol). The mixture is purged to with argon andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)(95.05 mg, 0.13 mmol) is added and stirred at 90° C. for 2 h. Thereaction mixture is filtered and concentrated. The residue is dilutedwith dichlormethane and water. The organic layer is separated, dried andconcentrated. The crude product is purified by reversed phase HPLC.Yield 12%.

Step 2: Synthesis of Example 344 (See Method A5, Step 3)

To I-20.1 (53 mg, 0.1 mmol) in acetonitrile (8 mL) p-toluenesulfonicacid monohydrate (68.70 mg, 0.36 mmol) is added and stirred at r.t. for6 h. The mixture is concentrated, diluted with methanol and purified byreversed phase HPLC. Yield 28%, m/z 414 [M+H]+, rt 0.74 min, LC-MSMethod 004_CA05.

Method Z Synthesis of(1S,2S,4R)-N-[1-cyano-2-(3-fluorophenanthridin-8-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamideExample 315

Step 1: Synthesis of Intermediate I-21.1

To I_(—)18.1 (1.5 g, 2.7 mmol) in anhydrous THF (1 mL) under argonatmosphere lithium borhydride (59 mg, 2.7 mmol) is added. The mixture isheated to 50° C. overnight. The reaction mixture is carefully dilutedwith water and extracted with ethyl acetate. The organic layer isseparated, dried and concentrated. The crude residue is filtered througha pad of silica gel (cyclohexane/ethyl acetate 1:2). Yield 37%.

Step 2: Synthesis of Intermediate I-21.2

To I-21.1 (260 mg, 0.495 mmol) in anhydrous ACN (5 mL)5-fluoro-2-iodo-aniline (117.28 mg, 0.495 mmol), 1,1bis(diphenylphosphino)ferrocene palladium dichloride (36.21 mg, 0.049mmol) and a solution of sodium carbonate in water 2 mol/L (0.742 mL,1.48 mmol) are added and purged with argon and heated to 80° C. for 1 h.The reaction mixture is diluted with DCM and water. The organic layer isseparated, dried and concentrated. The crude residue is purified byreversed phase HPLC. Yield 41%, m/z 509[M+H]+, rt 0.66 min, LC-MS MethodX011_S03.

The following intermediate as shown in Table 36 is synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 36 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-21.2.1 I-21.1

491 0.63 X011_S03

Step 3: Synthesis of Intermediate I-21.3

To I-21.2 (103 mg, 0.2 mmol) in DCM manganese(IV)oxide (153.65 mg, 8.73mmol) is added under cooling. The reaction mixture is stirred at r.t.overnight and 1 h at 50° C. Another manganese(IV)oxide (50 mg, 2.84mmol) is added and stirred for further 2 h at 50° C. The reactionmixture is filtered through a pad of cellulose and concentrated invacuo. The residue is purified by reversed phase HPLC.

Yield 27%.

The following intermediate as shown in Table 37 is synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 37 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-21.3.1 I-21.2.1

n.d. n.d. n.d.

Step 4: Synthesis of Example 315

To I-21.3 (26.4 mg, 0.054 mmol) in acetonitrile, p-toluenesulfonic acidmonohydrate (35.98 mg, 0.189 mmol) is added and stirred for 5 h. Thereaction solution is purified by reversed phase HPLC. Yield 60%, m/z 389[M+H]+, rt 0.37 min, LC-MS Method X12_S01.

Synthesis of Starting Materials/Educts Synthesis of tert-butylN-[(1S)-2-amino-1-[(4-bromo-2-fluoro-phenyl)methyl]-2-oxo-ethyl]carbamate(R1)

Step 1: Synthesis of Intermediate I-11.1

R24 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to−78° C. Then n-butyllithium (2.5 M in hexanes, 552 mL, 1381 mmol) isadded dropwise, keeping the temperature below −78° C. After 30 min R25(324 g, 1209 mmol) in tertahydrofurane (dry) (120 mL) is added dropwise.The reaction mixture is stirred at −78° C. for 1 h. The mixture isquenched with saturated NH₄Cl solution and extracted three times withethyl acetate. The organic layer is washed with brine, dried over Na₂SO₄and evaporated in vacuo. The residue is purified by flash chromatography(heptane/ethyl acetate=80/20). Yield 60%.

Step 2: Synthesis of Intermediate I-11.2

To I-11.1 (104 g, 265 mmol) in acetonitrile (600 mL) aq. 0.2 M HC (2788mL, 558 mmol) is added.

The mixture is stirred at RT for 12 h. The mixture is extracted withdiethylether and the pH of the aq. layer is adjusted to ˜8 with sat.NaHCO₃-solution. Then it is extracted three times with ethyl acetate.The organic layer is washed with brine, dried over Na₂SO₄ andconcentrated. Yield 80%.

Step 3: Synthesis of Intermediate I-11.3

I-11.2 (62.4 g, 211 mmol) is stirred in aq. 3 M HCl (3 mol/L, 1000 mL)at 60° C. for 16 h. The mixture is cooled down and the pH is adjusted to˜7 with aq. 6 M NaOH. Then the reaction mixture is filtered, washedthree times with water and dried in a vacuum oven at 40° C. for 12 h.Yield 74%.

Step 4: Synthesis of Intermediate I-11.4

To I-11.3 (151 g, 546 mmol) in 1,4-dioxane (2.2 L) is added aq. 2 Msodium carbonate (301 mL) and di-tertbutyl dicarbonate (138 g, 147 mL).The mixture is stirred for 4 h. Then water is added and the pH isadjusted to ˜4-5 with citric acid. The mixture is extracted three timeswith ethyl acetate. The organic layer is washed with brine, dried overNa₂SO₄ and concentrated. The residue is stirred in heptane for 15 minand the product is filtered off. Yield 87%.

Step 5: Synthesis of R1

To I-11.4 (181 g, 476 mmol) in dry DMF (1200 mL) N-methylmorpholine (72g, 713 mmol) and TBTU (153 g, 476 mmol) are added and the reactionmixture is stirred for 30 min. Then the reaction mixture is cooled to 0°C. and aq. 35% ammonium chloride solution (47 mL, 856 mmol) is added andthe mixture is stirred at room temperature for 12 h. Water is added andthe formed product is filtered off and washed three times with water.The product is dried in a vacuum oven at 40° C. for 72 h. Yield 64%.

The following intermediate as shown in Table 38 is synthesized in asimilar fashion from the appropriate intermediates:

TABLE 38 m/z r LC-MS Intermediate Structure [M + H]+ (min) method R1.1

409 1.05 V011_S01 R1.2

217 [M + H − BOC]+ 0.69 Z018_S04

Synthesis of(1S,2S,4R)-3-[(tert.-butoxy)carbonyl]-3-azabicyclo[2.2.1]heptane-2-carboxylate(R5)

The compound is commercially available or can be synthesized in analogyto Tararov et al, Tetrahedron Asymmetry 13 (2002), 25-28.

Step 1: Synthesis of R5C

A solution of R5A (44.9 g, 0.44 mol), freshly distilled from acommercially available solution in toluene (at 50 mbar, 55° C.) indiethylether (300 ml) is cooled at −10° C., followed by dropwiseaddition of R5B (53 g, 440 mmol), keeping the temperature below 0° C.After complete addition, MgSO4*H20 (91 g, 660 mmol) is added, and theresulting mixture stirred at room temperature overnight. The mixture isfiltrated, the solution phase concentrated in vacuo and the residuedistilled under reduced pressure to yield R5C (47 g, m/z 206 [M+H]+, rt1.29 min, LC-MS Method V003_(—)003). The product is used without furtherpurification.

Step 2: A solution of R5C (47 g; 229 mmol) and R5D (30 g; 458 mmol)(freshly distilled from dicyclopentadien) in DMF (150 ml) and 120 μlwater is cooled to 0° C., before TFA (18 ml; 234 mmol) is addeddropwise. The mixture is stirred overnight at room temperature, thenadded to a solution of 40 g NaHCO3 in 1200 ml water and extracted withdiethylether. The organic layer is separated, washed subsequently withaqueous NaHCO3 and water, dried over MgSO4, and concentrated in vacuo.The residue is worked up by column chromatography on silica(cyclohexane/ethyl acetate=9:1) to yield R5E (Yield 52% m/z 272 [M+H]+,rt 0.42 min, LC-MS Method X001_(—)004)Step 3: To a solution of R5E (24.8 g, 91 mmol) in ethanol (250 ml),Raney-nickel is added (2.5 g) and reacted at 50 psi under a hydrogenatmosphere at room temperature. The catalyst is filtered of, thesolution concentrated in vacuo and the residue worked up bychromatography on silica (cyclohexane/ethyl acetate 9:1). Afterevaporation of the organic solvent, the obtained product is redissolvedin diethylether and triturated with solution of HCl in dioxane,concentrated in vacuo, redissolved in 200 ml ethanol and concentrated invacuo to yield R5F: (Yield 78% m/z 274 [M+H]+, rt 0.42 min, LC-MS MethodX001_(—)004).Step 4: To a solution of R5F (22 g, 71 mmol) in ethanol (250 ml), 10%Pd/C is added (2.5 g) and reacted at 15 bar under a hydrogen atmosphereat room temperature. The catalyst is filtered of, the solutionconcentrated in vacuo. The residue is washed with diisopropylether toyield R5G. (Yield 98% m/z 170 [M+H]+, rt 0.48 min, LC-MS MethodV001_(—)007).Step 5: To R5G in a solution of triethylamin (24.6 ml), THF (150 ml) andwater (2 ml), R5I (15.9 g; 73 mmol) is added and the resulting mixturestirred for 40 hours at room temperature, then concentrated in vacuo.Ethyl acetate is added to the residue, subsequently extracted withwater, 1 N acidic acid and water, before the organic layer is dried overMgSO4 and concentrated in vacuo to yield R5I. (Yield 95% m/z 270 [M+H]+,rt 1.33 min, LC-MS Method V003_(—)003).Step 6: A mixture of R5I (16.9 g; 63 mmol) in acetone (152 ml), water(50 ml) and lithium hydroxide (3 g, 126 mmol) is stirred overnight atroom temperature. Water (100 ml) was added, the volume reduced in vacuobefore cooling to 0° C. followed by the addition of 1N aqueous HCl toacidify to a pH of 2-3, immediately followed by extraction with ethylacetate. The organic layer was washed with water, dried (MgSO4) andconcentrated. To the residue, dichloromethane (100 ml) and cyclohexane(100 ml) was added, the volume reduced in vacuo by half and the mixtureto temperated at 15° C. The precipitate was filtered of, washed withcyclohexane to yield R5 (Yield 66%, m/z 242 [M+H]+).

Synthesis of (2S)-2-amino-3-(4-bromo-2-fluoro-phenyl)propanamide (R6)

To R1 (10.0 g, 27.7 mmol) in DCM (70 mL) TFA (25 mL, 162.0 mmol) isadded and the reaction mixture is stirred for 12 h. Then the reactionmixture is concentrated, the residue is dissolved in DCM anddiisopropylether is added. The product precipitates and is filtered bysuction and washed with diisopropylether. Yield>95% m/z 261 [M+H]+, rt0.67 min, LC-MS Method V018_S01.

The following intermediate as shown in Table 38.1 is synthesized in asimilar fashion from the appropriate intermediates:

TABLE 38.1 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodR6.1

217 0.08 Z011_S03

For R6.1 the reaction time is 2 h. After the reaction mixture isconcentrated, the crude residue is freeze-dried and used without furtherpurification for the next step.

Synthesis of 2-Amino-3-(1H-indazol-5-yl)propanamide (R14)

Step 1: Synthesis of Intermediate I-8.3

1,1,3,3-Tetramethylguanidin (0.44 mL, 3.51 mmol) in THF (5 mL) is cooleddown to −70° C. Educt R22 (1.00 g, 3.36 mmol) is dissolved in 5 mL THFand is added. The mixture is stirred for 5 min before R15 (0.49 g, 3.36mmol)—also dissolved in 5 mL THF—is added dropwise. The cooling isremoved and the mixture warms up to room temperature. The reactionmixture is heated to 80° C. for 12 h. Because of remaining eductTetramethylguanidin and R22 are added twice and the mixture is stirredat 80° C. for additional 4 h. The reaction mixture is concentrated.Ethyl acetate and water are added to the residue. 1 M sulfuric acid isadded and the organic layer is separated, is dried over MgSO₄ andconcentrated. Yield 87%, m/z 318 [M+H]+, rt 0.97 min, LC-MS MethodV011_S01.

The following intermediate as shown in Table 39 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 39 Inter- medi- m/z rt LC-MS ate Structure [M + H]+ (min) methodI-8.3.1

318 1.00 V012_S01

Step 2: Synthesis of Intermediate I-8.4

To I-8.3 (925 mg, 2.91 mmol) in methanol (30 mL) Pd/C (10%, 130 mg) isadded. The reaction mixture is stirred under hydrogen (3 bar) for 16 h.Then the mixture is filtered and the filtrate is concentrated. Theresidue is triturated with diethyl ether and the product is filtered bysuction. Yield 88%, m/z 320 [M+H]+, rt 0.99 min, LC-MS Method V011_S01.

The following intermediate as shown in Table 40 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 40 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-8.4.1 I-8.3.1

320 0.96 V011_S01

Step 3: Synthesis of Intermediate I-8.5

To I-8.4 (820 mg, 2.57 mmol) in methanol (15 mL) sodium hydroxidesolution (2.5 mL, 1 mol/L) is added. The reaction mixture is heated to40° C. for 2 h. The mixture is concentrated partially and 1 M HCl isadded to neutralization. The precipitation is filtered with suction, isdissolved in methanol and concentrated quickly. Yield 65%, m/z 306[M+H]+, rt 0.57 min, LC-MS Method V011_S01.

The following intermediate as shown in Table 41 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 41 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) methodI-8.5.1 I-8.4.1

306 0.55 V011_S01

Step 4: Synthesis of Intermediate I-8.6

To I-8.5 (400 mg, 1.31 mmol) in DMF (5 mL) diisopropylethylamine (502μL, 2.88 mmol) and is TBTU (421 mg, 1.31 mmol) are added and thereaction mixture is stirred for 15 min. Then aq. 30% ammonia solution(545 μL, 9.61 mmol) is added and the mixture is stirred for additional12 h. Water is added to the reaction mixture and extracted with ethylacetate. The organic layer is washed with brine and saturated NaHCO₃solution, is dried over MgSO₄ and concentrated. Yield 55%, m/z 305[M+H]+, rt 0.75 min, LC-MS Method V011_S01.

The following intermediate as shown in Table 42 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 42 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-8.6.1 I-8.5.1

327 [M + Na]+ 0.77 V011_S01 I-8.6.2 commerically available

315 n.d. n.d.

For I-8.6.2 N-methylmorpholine is used instead of diisopropylethylamine(in analogy to synthesis of R1)

Step 5: Synthesis of R14

To I-8.6 (130 mg, 0.43 mmol) in DCM (3 mL) TFA (358 μL, 0.47 mmol) isadded and the reaction mixture is heated to 30° C. for 12 h. Then thereaction mixture is concentrated. Yield>95%.

The following intermediate as shown in Table 43 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 43 Inter- m/z medi- [M + rt LC-MS ate Educt Structure ofIntermediate H]+ (min) method R14.1 I-8.6.1

227 [M + Na]+ 0.53 V011_S01 R14.2 I-8.6.2

214 0.31 X012_S01

Synthesis of 5-bromo-2-methyl-isoindoline (R4)

The pH of a mixture of R26 (1.85 g, 7.9 mmol) in methanol (100 mL) andwater (10 mL) is adjusted to ˜5 with acetic acid. Then a 37% formalinsolution (1.28 mL, 15.8 mmol) is added and the mixture is stirred for 15min. Sodium cyanoborohydride (0.74 g, 11.8 mmol) is added and thereaction mixture is stirred for additional 12 h. The mixture isconcentrated and ethyl acetate and aq. 1 M NaOH solution are added tothe residue. The organic layer is washed with NaCl solution, dried overMgSO₄ and concentrated. The residue is dissolved in diethyl ether andethereal HCl is added dropwise. The resulting precipitate is filteredoff. Yield 62% m/z 212/214 [M+H]+, rt 0.65 min, LC-MS Method V012_S01.

Synthesis of 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine (R34)

R33 (800 mg, 3.1 mmol) is dissolved in DCM, N-methyl-piperazine (313 mg,3.1 mmol) is added and stirred for 12 h. After addition of 2 mL 1N HClunder stirring the phases are separated. The organic phase is dried overMgSO₄ and after filtration evaporated in vacuo. Yield: 84% m/z 319(M+H)+.

The following intermediates as shown in Table 44 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 44 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method R34.1 R33

304 n.d. n.d. R34.2 R33

306 n.d. n.d. R34.3 R33

340 0.64 X012_S01 R34.4

337/339 0.36 X012_S01 R34.5

333/335 0.36 X012_S01

For R34.4 and R34.5 additional 2 eq. of DIPEA are added to the reactionmixture.

Synthesis of Reagent R37

Step 1: Synthesis of R36

R35 (200 μL, 1.448 mmol) is dissolved in 10 mL methanol. Cyanamide(79.112 mg, 1.882 mmol), potassium tert-butoxide (194.9 mg, 1.737 mmol)and N-bromosuccinimide (386.282 mg, 2.171 mmol) are added and stirredfor 1 h at room temperature. The product is purified by preparative HPLC(Waters 30×100 mm, 10 μm, sunfire RP18, acetonitrile/water/TFA). Thefractions containing the product are combined and lyophilized. Yield87%, m/z 244 [M+H]+, rt 0.62 min, LC-MS Method Z018_S04.

In analogy the following reagent as shown in Table 45 is prepared:

TABLE 45 m/z LC-MS Intermediate Educt Structure of Intermediate [M + H]+rt (min) method R36.1 commerically available

243 0.64 Z018_S04

Step 2: Synthesis of R37

R36 (335 mg, 1.378 mmol) is dissolved in 3 mL ethanol. Potassiumcarbonate (571.315 mg, 4.134 mmol) and 3-chloroperbenzoic acid (356.696mg, 2.067 mmol) are added at 0° C., and the mixture is stirred for 2 hat room temperature. The solvent is evaporated in vacuo and the residueis dissolved in DMF. The product is purified by preparative HPLC (Waters30×100 mm, 10 μm, sunfire RP18, acetonitrile/water/TFA). The fractionscontaining the product are combined and lyophilized. Yield 71%, m/z 260[M+H]+, rt 0.68 min, LC-MS Method Z018_S04.

In analogy the following reagent as shown in Table 46 is prepared:

TABLE 46 Inter- medi- m/z rt LC-MS ate Educt Structure of Intermediate[M + H]+ (min) method R37.1 R36.1

259 0.67 Z011_S03

Synthesis of1-[3-[4-(bromomethyl)-3-fluoro-phenyl]-5-methyl-prazol-1-yl]ethanone(R13)

Step 1: Synthesis of Intermediate I-13.1

To potassium tert.-butylate (7.4 g, 65.6 mmol) in anhydrous THF (300 mL)is added crown ether 18-6 (12.2 g, 46.0 mmol). The mixture is cooleddown to 0° C. and R28 (5.0 g, 32.9 mmol) is added and stirred for 15 minat room temperature. Then acetic acid methyl ester (5.2 mL 65.7 mmol) isadded and the reaction mixture is stirred for additional 1 h. Themixture is concentrated and the residue is purified via flashchromatography (cyclohexane/ethyl acetate=95:5). Yield 79%, m/z 195[M+H]+, rt 0.66 min, LC-MS Method V011_S01.

Step 2: Synthesis of Intermediate I-13.2

To I-13.1 (5.1 g, 26.1 mmol) 1 M hydrazine solution in THF (78.2 mL,78.2 mmol) is added and the reaction mixture is heated to 80° C. for 12h. The reaction mixture is concentrated and the residue is purified viaflash chromatography (cyclohexane/ethyl acetate=70:30). Yield 90%, m/z191 [M+H]+, rt 1.01 min, LC-MS Method V011_S01.

Step 3: Synthesis of Intermediate I-13.3

I-13.2 (1.00 g, 5.3 mmol) and acetic acid anhydride (5.00 mL, 53.0 mmol)are stirred for 12 h. Water and methanol are added to the reactionmixture, the precipitate is filtered by suction and dried in vacuo.Yield 87%, m/z 233 [M+H]+, rt 1.31 min, LC-MS Method V011_S01.

Step 4: Synthesis of R13

To I-13.3 (0.95 g, 4.1 mmol) in DCM (25 mL) is added N-bromo succinimide(0.80 g, 4.5 mmol) and 2,2′-azobis(isobutyronitrile) (50 mg). Thereaction mixture is refluxed for 12 h under radiation with an Hg lamp.The mixture is concentrated and the residue is purified via flashchromatography (cyclohexane/DCM=75:25). Yield 39%, m/z 311 [M+H]+, rt1.43 min, LC-MS Method V018_S01.

Synthesis of 6-bromo-2-methyl-3,4-dihydroisoquinolin-1-one (R32)

R31 (500 mg, 2.2 mmol) in DMF (3 mL) is cooled down to 0° C. Under argonatmosphere NaH (60%, 121 mg, 3.0 mmol) is added and stirred for 20 min.Then methyl iodide (0.275 mL, 4.4 mmol) is added and the mixture isstirred for additional 1 h at 0° C. Ice water is added to the reactionmixture and the precipitate is filtered by suction and dried at 50° C.in the vacuum oven for 12 h. Yield 73%, m/z 240/242 [M+H]+, rt 0.89 min,LC-MS Method V012_S01.

Synthesis of tert-butyl 2-(bromomethyl)-9H-carbazole-9-carboxylate(R13.1 for synthesis of I-7.1.3)

Step 1: Synthesis of Intermediate I-15.1

3-Methyl-diphenylamine R38 (1.0 g, 5.5 mmol), K₂CO₃ (75 mg, 0.55 mmol)and palladium acetate (37 mg, 0.16 mmol) in 2,2-dimethyl-1-propanol (5mL) is stirred at 110° C. for 14 h. Water is added to the reactionmixture and extracted with dichloromethane. The combined organic layeris concentrated in vacuo, residue triturated withmethanol/dichloromethane and dried in vacuo and directly taken to thenext step. Yield 29%, m/z 182 [M+H]+, rt 0.67 min, LC-MS MethodX012_S01.

Step 2: Synthesis of Intermediate I-15.2

I-15.1 (285 mg, 1.6 mmol), di-tert.-butyl dicarbonate (412 mg, 1.9 mmol)and DMAP (50 mg, 0.41 mmol) in dichloromethane (10 ml) are stirred atroom temperature for 16 hours. The reaction mixture extracted withwater, the organic layer is separated and concentrated in vacuo anddirectly taken to the next step. Yield 86%, m/z 282 [M+H]+, rt 0.89 min,LC-MS Method X012_S01.

Step 3: Synthesis of Intermediate R13.1

I-15.2 (380 mg, 1.4 mmol), N-bromosuccinimide (289 mg, 1.6 mmol), AIBN(20 mg, 0.12 mmol) in tetrachloromethane (5 mL) is heated to reflux over16 h. Water and dichloromethane are added to the reaction mixture, theorganic layer separated and concentrated. The residue is triturated withmethanol and used directly in the next step. Yield 41%, m/z 360 [M+H]+,rt 0.67 min, LC-MS Method V0110_S01.

Synthesis of tert-butyl 3-(chloromethyl)-9H-carbazole-9-carboxylat(R13.2 for synthesis of I-7.1.6)

Step 1: Synthesis of Intermediate I-16.1

9H-Carbazole-3-carboxylic acid R39 (500 mg, 2.4 mmol), in methanol (20mL) is cooled to 0° C. Thionylchloride (206 ml, 2.8 mmol) is addeddropwise to the stirred mixture at this temperature. The mixture is thenstirred at room temperature for 16 hours. The formed precipitate isfiltered and dried in vacuo and directly taken to the next step. Yield53%, m/z 226 [M+H]+, rt 0.59 min, LC-MS Method X012_S01.

Step 2: Synthesis of Intermediate I-16.2

I-16.1 (280 mg, 1.2 mmol), di-tert.-butyl dicarbonate (326 mg, 1.5 mmol)and DMAP (50 mg, 0.41 mmol) in dichloromethane (10 ml) are stirred atroom temperature for 16 hours. The reaction mixture extracted withwater, the organic layer is separated and concentrated in vacuo anddirectly taken to the next step. Yield 99%, m/z 326 [M+H]+, rt 0.84 min,LC-MS Method X012_S01.

Step 3: Synthesis of Intermediate I-16.3

I-16.2 (400 mg, 1.2 mmol) and boronhydride-tetrahydrofuran addukt (1.2ml 1M in THF, 1.2 mmol) are dissolved in THF (5 ml). LiBH4 is repeatedlyadded in small portions at 50° C., until HPLC shows completion ofreaction. Water and dichloromethane are added to the reaction mixture,the organic layer separated, concentrated. and purified via HPLC. Yield40%, m/z 280 [M−H2O+H]+, rt 0.70 min, LC-MS Method X012_S01.

Step 4: Synthesis of Intermediate R13.2

I-16.3 (145 mg, 0.5 mmol) and DIPEA (171 μl, 1.0 mmol) are dissolved indichloromethane (10 ml) and cooled to −10° C. Methanesulfonylchloride(46 μl, 0.6 mmol) in dichloromethane (1 ml) is added dropwise. Aftercomplete addition, the mixture is stirred for 16 h at room temperature.Water is added to the reaction mixture, the organic layer separated,concentrated in vacuo to yield R13.2, which is directly taken to thenext step. Yield 73%, rt 0.87 min, LC-MS Method X012_S01.

Synthesis of 2-(chloromethyl)-9,10-dihydrophenanthrene (R13.3 forsynthesis of I-7.1.4)

Step 1: Synthesis of Intermediate I-17.1

2-Acetyl-9,10-dihydro-phenanthren R40 (1.0 g, 4.5 mmol) is added tosolution of bromine (924.7 μl, 18 mmol) and KOH (3.3 g, 58.5 mmol) inwater (20 ml) at 0° C. After addition is completed, the reaction mixtureis heated to 55° C. for 16 hours. The mixture is cooled to r.t.,extracted with dichloromethane. The aqueous phase is separated,acidified with 1 M HCl aq and the precipitating product is filtered offand dried in vacuo at 50° C. Yield 92%, m/z 225 [M+H]+, rt 0.62 min,LC-MS Method X012_S01.

Step 2: Synthesis of Intermediate I-17.2

I-17.1 (930 mg, 4.2 mmol) is dissolved in THF (10 ml), CDI (874 mg, 5.4mmol) is added in small portions and the mixture is stirred for 1 h at50° C. The mixture is added slowly to sodium borohydride (470 mg, 12.4mmol) in ice water, so that the temperature remains below 10° C. Themixture is stirred for 16 hours at r.t. and extracted withdichloromethane/water. The organic layer is separated and concentratedin vacuo, the remaining crude product purified via HPLC. Yield 53%, m/z210 [M]+, 193 [M−H₂O]+, rt 0.61 min, LC-MS Method X012_S01.

Step 3: Synthesis of Intermediate R13.3

I-17.2 (460 mg, 2.2 mmol), DIPEA (766 μl, 4.4 mmol) are dissolved indichloromethane (10 ml) and cooled to −10° C. Methanesulfonylchloride(207 μl, 2.6 mmol) in dichloromethane (1 ml) is added dropwise. Aftercomplete addition, the mixture is stirred for 16 h at room temperature.Water is added to the reaction mixture, the organic layer separated,concentrated in vacuo and the is remaining crude product purified viaHPLC. Yield 67%, m/z 228 [M]+, rt 0.79 min, LC-MS Method X012_S01.

Synthesis of 6-Aza-tricyclo[3.2.1.0*2,4*]octane-6,7-dicarboxylic acid6-tert-butylester (R6.2)

Step 1: Synthesis of Intermediate R29.2

Dicyclopenta-1,3-diene is cracked and distilled at 42° C. and 1013 mbarto give cyclopenta-1,3-diene.

Ethyl 2-oxoacetate is also freshly distilled from a commerciallyavailable solution in toluene. Assumed concentration is 50%.

To N-boc-imino-(triphenyl)phosphorane (11.32 g, 30.00 mmol) in toluene(100 mL) is added ethyl 2-oxoacetate (15 mL, 60.00 mmol) andcyclopenta-1,3-diene (5 mL, 60.00 mmol) and stirred overnight at r.t.The reaction mixture is concentrated and the crude residue is purifiedover silica gel (cyclohexane/ethyl acetate 7:3). Yield 16%

R29.2. can be obtained through preparative chiral chromatography fromthis mixture of R29.1 and R29.2 (table 46.1) using method Chiral SFC G

TABLE 46.1 Intermediate Structure of Intermediate R29.1

R29.2

Step 2: Synthesis of Intermediate I-14.1

To R29.2 (5.00 g, 18.7 mmol) in diethylether (100 mL) is addedpalladium(II) acetate (0.42 g, 1.87 mmol). Under stirring diazomethanesolution in diethylether (62 mmol) is added. The reaction mixture isstirred for 12 h. To destroy remaining diazomethane, silica gel and 3 mLacetic acid are added. Then the mixture is stirred for additional 1 hand filtrated. The solution is concentrated and extracted with DCM,water and brine. Yield 98%, m/z 226 [M+H−tButyl]+, rt 0.64 min, LC-MSMethod X012_S01.

Step 3: Synthesis of R6.2

To I-14.1 (5.40 g, 19.2 mmol) in dioxane (60 mL) is added aq. 4 M NaOH(20 mL, 80 mmol). The reaction mixture is heated to 50° C. for 3 h. Themixture is extracted two times with DCM, then the water layerneutralized with 2 M HCl and extracted three times with DCM. Thecombined organic layers are dried over MgSO₄ and concentrated. Theresidue is dissolved in diethylether and evaporated, the productcrystallizes. Yield 88%, m/z 198 [M+H−tButyl]+, rt 0.48 min, LC-MSMethod X012_S01.

Synthesis of1-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(R7)

Step 1: Synthesis of Intermediate I-12.1

To R27 (25.0 g, 111 mmol) in acetonitrile (750 mL) is added MeI (15 mL,241 mmol) and K₂CO₃ (60.0 g, 434 mmol) and the reaction mixture isstirred at 60° C. for 2 h. The reaction mixture is filtered andconcentrated. Water and ethyl acetate are added to the residue. Theorganic layer is extracted twice with water, dried over MgSO₄ andconcentrated. Yield 56%, m/z 240/242 [M+H]+, rt 0.48 min, LC-MS MethodX001_(—)004.

The following intermediates as shown in Table 47 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 47 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodI-12.1.1

311/313 0.362 Z020_S01 I-12.1.2

n.d. n.d. n.d. I-12.1.3

211/213 0.55 X012_S01 I-12.1.4

n.d. n.d. n.d. I-12.1.5

245 0.21 X012_S01 I.12.1.6

n.d. n.d. n.d. I-12.1.7

268 0.71 X012_S01 I-12.1.8

211/213 0.55 X012_S01

For I-12.1.1, I-12.1.2, I-12.1.3, I-12.1.5, I-12.1.7 and I-12.1.8 sodiumhydride and DMF is used instead of potassium carbonate and ACN.

For I-12.1.3, I-12.1.7 and I-12.1.8 the reaction temperature is r.t.

For I-12.1.4 DMF is used.

For I-12.1.6 the reaction conditions differ:1,1-Difluoro-2-trifluoromethanesulfonyl-ethane is used as alkylationreagent in triethylamin as solvent at r.t.

Step 2: Synthesis of Intermediate I-12.2

I-12.1 (15.0 g, 63 mmol) and hydrazine hydrate (30 mL, 618 mmol) areheated to 125° C. for 72 h. To the cool reaction mixture DCM is addedand extracted with water and 1 M HCl. The organic layer is dried overMgSO₄ and concentrated. The crystallized residue is dissolved in DCM,methanol is added and the DCM is removed in vacuo. The crystallizedproduct is filtered by suction and washed with cold methanol. Yield 63%,m/z 226/228 [M+H]+, rt 1.16 min, LC-MS Method V001_(—)003.

The following intermediates as shown in Table 48 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 48 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodI-12.2.1

n.d. n.d. n.d. I-12.2.2

283/285 0.832 n.d. I-12.2.3

n.d. n.d. n.d.

Step 3: Synthesis of Intermediate R7

To I-12.2 (32.0 g, 142 mmol) in anhydrous dioxane (400 mL) is added R3(54.4 g, 241 mmol) and potassium acetate (41.6 g, 424 mmol). The mixtureis purged with Argon,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complexwith dichloromethane (11.2 g, 14 mmol) is added and the mixture isheated to 90° C. for 2 h. The reaction mixture is diluted with ethylacetate and water, the organic layer is washed with water, dried overMgSO₄ and concentrated. The residue is purified via flash chromatography(cyclohexane/EA=70:30). Yield 72%, m/z 274 [M+H]+, rt 0.67 min, LC-MSMethod V011_S01.

The following intermediates as shown in Table 49 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 49 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method R7.1

325 [M + NH₄]+ 0.30 X018_S01 R7.2

276 [M + H]+ 0.94 X002_002 R7.3

n.d. n.d. n.d. R7.4

318 0.92 Z018_S04 R7.5

302 n.d. n.d. R7.6

294 0.85 Z018_S04 R7.7

260 0.65 X001_004 R7.8

n.d. n.d. n.d. R7.9

280 0.63 X001_002

Synthesis of Boronic Ester R7.6

2 g (10.3 mmol)4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2.9 mL(20.6 mmol) 4-(iodomethyl)-tetrahydro-2H-pyran are dissolved in 200 mLDMF and 4.274 g (30.9 mmol) K₂CO₃ are added. The mixture is shaken at80° C. for 5 h. After cooling to r.t. the mixture is filtered, thefiltrate is concentrated in vacuo to approximately 60 mL. The product isseparated using HPLC-MS (Gilson, mass flow 120 mL/min, 10 μm, 200 gSunfire RP18, ACN/water/TFA). The product fractions are combined andfreeze-dried to yield 115 mg product (3.8%) R7.6.

Synthesis of Boronic Ester R7.8

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.56 mmol)and pyridine (10 mL) are cooled down with an ice bath. Methanesulfonylchloride (0.933 mL, 12.01 mmol) is dissolved in dichlormethane (10 mL)and added slowly dropwise. The reaction mixture is allowed to come toroom temperature and concentrated. The residue is diluted withdichlormethane and water. The organic layer is separated, dried andconcentrated. The crude product is used without further purification.Yield: >95%

Synthesis of Boronic Ester R7.9

Under nitrogen atmosphere to sodiumhydride (50%) (0.218 g, 4.54 mmol)and DMF (3 mL) is added4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.5 g, 2.5mmol) and stirred for 30 min at r.t. N-(2-chloroethyl)acetamide (0.775mL, 7.52 mmol) is added and stirred at 90° C. overnight. Due to noreaction N-(2-chloroethyl)acetamide (0.26 mL) and copper(I)iodide (25mg, 0.13 mmol) are added and stirred at 90° C. for 24 h. The reactionmixture is diluted with methanol, filtered through a thiol cartridge andconcentrated. The crude product is used without further purification.Yield: 100%

All other boronic acid derivatives R9 and R16 and alkynes R10 arepurchased or prepared by literature known procedures.

Synthesis of tert-butyl(1S,2S,4R)-2-(1-methoxycarbonylvinylcarbamoyl)-3-azabicyclo[2.2.1]heptane-3-carboxylate(R41)

Step 1: Synthesis of Intermediate I-22.1

To R5 (500 mg, 2.07 mmol) in DMF (5 mL) are added HATU (866.72 mg, 2.28mmol) and DIPEA (1.43 mL, 8.29 mmol) and stirred at r.t. for 15 min. Tothe reaction mixture is added methyl 2-amino-3-hydroxy-propanoatehydrochloride (354.64 mg, 2.28 mmol) and stirred at r.t. for 4 h. Thereaction mixture is diluted with ACN and water and purified by reversedphase HPLC.

Yield 79%, m/z 343 [M+H]+, rt 0.44 min, LC-MS Method X011_S03.

Step 2: Synthesis of R41

I-22.1 (100 mg, 0.29 mmol) is dissolved in dichlormethane (2 mL) andcooled down to 0° C. 4-dimethylamino pyridine (1.78 mg, 0.015 mmol), TEA(65.13 μL, 0.47 mmol) and methansulfonyl chloride (29.59 μL, 0.38 mmol)are added and stirred at r.t. for 3 h. The reaction mixture is dilutedwith sodium carbonate solution. The organic layer is separated, driedand concentrated. The crude residue is purified by reversed phase HPLC.

Yield 27%, m/z 324 [M+H]+, rt 0.63 min, LC-MS Method X011_S03.

Synthesis ofmethyl(E)-2-(benzyloxycarbonylamino)-3-[4-(1,4-dimethyl-4-piperidyl)-2-fluoro-phenyl]prop-2-enoate(R42)

Step 1: Synthesis of Intermediate I-23.1

To 1-fluoro-2-methoxy-benzene (25 mL, 222.79 mmol) and1,4-dimethylpiperidin-4-ol (7 g, 54.18 mmol) is addedtrifluoromethanesulfonic acid (50 mL, 565.04 mmol) under ice bathcooling. The reaction mixture is stirred at r.t. overnight, poured intoiced water and extracted with PE. To the aqueous phase is added solidsodium carbonate and extracted with ethyl acetate. The organic layer isdried and concentrated. The crude product is triturated withdiisopropylether and the to precipitate is filtered off. Yield 82%, m/z238 [M+H]+, rt 0.39 min, LC-MS Method X018_S02.

Step 2: Synthesis of Intermediate I-23.2

To I-23.1 (16.9 g, 43.63 mmol) in dichlormethane (150 mL) is added borontribromide 1M in dichlormethane (44 mL, 44 mmol) and stirred at r.t.overnight. The reaction mixture is diluted with dichlormethane and 10%K₂CO₃-solution. The resulting precipitate is filtered off. The aq. layeris repeatedly extracted with dichlormethane, the precipitate formed uponstanding at rt is filtered off and washed with dichlormethane. Thedichloromethane phase is concentrated and purified by reversed HPLC andfreeze dried. The isolated precipitates and the corresponding HPLCfractions are combined to yield the desired product.

Yield 18%, m/z 224 [M+H]+, rt 0.61 min, LC-MS Method V011_S01.

Step 3: Synthesis of Intermediate I-23.3

To I-23.2 (1.4 g, 6.27 mmol) in anhydrous dichlormethane (40 mL)triethylamine (1.8 mL, 12.985 mmol) is added and cooled down to −20° C.Trifluoromethanesulfonic acid anhydride (1.1 mL, 6.538 mmol) is addeddropwise and stirred at −10° C. for 30 min. The reaction mixture isdiluted with dichlormethane, washed with K₂CO₃-solution and brine. Theorganic layer is dried and concentrated. The crude product is used forthe next step without further purification. Yield 98%, m/z 356 [M+H]+,rt 1.30 min, LC-MS Method V011_S01.

Step 4: Synthesis of R42

2-benzyloxycarbonylamino-acrylicacidmethylester (2.274 g, 9.67 mmol),bis(dibenzylideneacetone) palladium (0) (295 mg, 0.32 mmol),(2-biphenylyl)di-tert-butylphosphine (345 mg, 1.156 mmol) and lithiumchloride (710 mg, 16.73 mmol) are purged with argon. I-23.3 (2.29 g,6.44 mmol) is dissolved in DMF (15 mL) and triethylamine are added andstirred at 80° C. overnight. The reaction mixture is concentrated, thendiluted with dichlormethane and washed with 5% K₂CO₃-solution. Theorganic layer is dried and concentrated. The crude product is purifiedby reversed phase HPLC.

Yield 33%, m/z 441 [M+H]+, rt 1.23 min, LC-MS Method V011_S01.

The following intermediate as shown in Table 50 is synthesized in ananalogous manner from the appropriate intermediate R41 and R91:

TABLE 50 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method R42.1

558 0.47 X018_S01

Synthesis of (2S)-2-amino-3-(4-benzyloxy-2-fluoro-phenyl)propanamidehydrochloride (R47)

Step 1: Synthesis of Intermediate I-24.1

R22 (22.58 g, 75.97 mmol) in Me-THF (50 mL) is cooled down to −10° C.,1,1,3,3-tetramethylguanidine (9.55 mL, 75.97 mmol) is added and stirredfor 30 min. 4-benzyloxy-2-fluoro-benzaldehyde (15.9 g, 69.06 mmol)dissolved in 100 mL Me-THF is added dropwise and stirred for 3 h at −10°C. to 0° C. The cooling is removed and the mixture warms up to roomtemperature.

The reaction mixture is diluted with 300 mL Me-THF and extracted withwater. The organic layer is treated with activated carbon, dried overMgSO₄ and concentrated.

The crude product is recrystallized with cyclohexane and filtered off.

Yield 97%, m/z 402 [M+H]+, rt 0.80 min, LC-MS Method X018_S01.

The following intermediate as shown in Table 50.1 is synthesized in ananalogous manner from the appropriate intermediates:

TABLE 50.1 m/z rt Intermediate Structure [M + H]+ (min) LC-MS methodI-24.1.1

374/376 0.77 X018_S02

Step 2: Synthesis of Intermediate I-24.2

I-24.1 (2.8 g, 6.98 mmol) and(+)-1,2-bis((2s,5s)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (250 mg, 0.346 mmol) in methanol (60 mL) arestirred under hydrogen (50 psi) at r.t. for 2 h. Then the mixture isfiltered and the filtrate is concentrated. Yield 100%, m/z 404 [M+H]+,rt 1.40 min, LC-MS to Method V001_S01.

The following intermediates as shown in Table 51 are synthesized in ananalogous manner from the appropriate intermediates:

TABLE 51 m/z rt Intermediate Structure [M + H]+ (min) LC-MS methodI-24.2.1

443 1.24 V011_S01 I-24.2.2

560 0.68 X011_S03 I-24.2.3

376 n.d. n.d.

Step 3: Synthesis of Intermediate I-24.3

I-24.2 (2.95 g, 6.95 mmol) is dissolved in anhydrous methanol (15 mL).Calcium chloride (812 mg, 7.32 mmol) and ammonia in methanol 7N (15 mL,10.5 mmol) is added and stirred at r.t. overnight. The reaction mixtureis diluted with water (45 mL) and the precipitate is filtered off andwashed with water.

Yield 90%, m/z 389 [M+H]+, rt 0.65 min, LC-MS Method X011_S03.

The following intermediate as shown in Table 52 is synthesized ananalogous manner from the appropriate intermediates:

TABLE 52 m/z rt Intermediate Structure [M + H]+ (min) LC-MS methodI-24.3.1

428 1.05 V011_S01 I-24.3.2

545 0.57 X011_S03 I-24.3.3

361/363 0.64 X018_S02Intermediate I-24.3.1 is purified by reversed phase HPLC.

Step 4: Synthesis of R47

To I-24.3 (2.42 g, 6.23 mmol) in dichlormethane (20 mL) is added HCl indioxane 4 mol/L (7.79 mL, 31.15 mmol) and stirred at r.t. for 3 h. Thereaction mixture is diluted with TBME and the precipitate is filteredoff and washed with TBME.

Yield 95%, m/z 289 [M+H]+, rt 0.50 min, LC-MS Method X011_S03.

The following intermediate as shown in Table 52.1 is synthesized in ananalogous manner from the appropriate intermediates:

TABLE 52.1 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodR47.1

261/ 263 0.31 X018_S02

Synthesis of(2S)-2-amino-3-[4-(1,4-dimethyl-4-piperidyl)-2-fluoro-phenyl]propanamideR49

I-24.3.1 (625 mg, 1.46 mmol) and Pd/C 10% (150 mg) in methanol (60 mL)is stirred under to hydrogen (50 psi) at r.t. for 3.5 h. The reactionmixture is filtered and concentrated.

Yield 99%, m/z 294 [M+H]+, rt 0.80 min, LC-MS Method V011_S01.

Synthesis of(1-ethyl-3,6-dihydro-2H-pyridin-4-yl)trifluoromethanesulfonate (R51)

The reaction is carried out under argon atmosphere.

Diisopropylamine (5.289 mL, 38 mmol) in anhydrous THF (25 mL) is cooleddown to −50° C. N-butyllithium in hexane 2.5M (13.786 mL, 34.47 mmol) isadded dropwise and stirred for 45 min, then the solution is allowed towarm up to 0° C. and cooled down to −50° C. again. 1-Ethyl-4-piperidone(4 g, 31.45 mmol) dissolved in 30 mL THF is added dropwise and stirredfor 30 min. R18 (11.797 g, 33.02 mmol) dissolved in 30 mL THF is addeddropwise. The cooling is removed and the reaction mixture stirred for 2h.

The reaction mixture is diluted with 50 mL toluene. The organic layer iswashed with 1N sodium hydroxide, halfsaturated brine, dried andconcentrated. The residue is purified over silica gel. Yield 15%, m/z260 [M+H]+, rt 0.30 min, LC-MS Method X012_S01.

The following intermediates as shown in Table 53 are synthesized in ananalogous manner from the appropriate intermediates:

TABLE 53 m/z rt Intermediate Structure [M + H]+ (min) LC-MS method R51.1

274 n.d. n.d. R51.2

n.d. n.d. n.d. R51.3

n.d. n.d. n.d. R51.4

322 1.41 V011-S01 R51.5

316 1.23 Z012_S04 R51.6

308 1.38 V11_S01

For Intermediate R51.2, R51.3, R51.4 and R51.6 the reaction conditionsdiffer: lithium bis(trimethylsilyl)amide is used and the reaction iscarried out at −78° C. The crude product is used for the next stepwithout further purification.

Intermediate R51.4 is purified over silica gel.

For Intermediate R51.5 the reaction conditions differ: lithiumbis(trimethylsilyl)amide is used and the reaction is carried out at −50°C. The crude product is purified over silica gel.

Synthesis of (5-ethyl-1-isobutyl-pyrazol-3-yl)trifluoromethanesulfonate(R54)

Step 1: Synthesis of Intermediate I-25.1

Ethyl pent-2-ynoate (300 μL, 2 mmol), isobutylhydrazine hydrate (240 μL,2 mmol), methanol (1 mL) and water (1 mL) are stirred together in themicrowave at 140° C. for 15 min.

The crude product is used for the next step without furtherpurification.

Step 2: Synthesis R54

Intermediate I-25.1 (380 mg, 2 mmol) is dissolved in anhydrousdichlormethane (10 mL), DIPEA (1.2 mL, 6.94 mmol) is added and cooleddown to 0° C. Trifluoromethylsulfonyl trifluoromethanesulfonate

(375 μL, 2.26 mmol) dissolved in dichlormethane is added dropwise andstirred for 45 min. Another trifluoromethylsulfonyltrifluoromethanesulfonate (188 μL, 1.13 mmol) is added and stirred for30 min. The reaction mixture is extracted with NaHCO₃-solution (5%). Theorganic layer is separated, dried and concentrated. The residue ispurified over silica gel.

Yield 21%, m/z 301 [M+H]+, rt 0.86 min, LC-MS Method X018_S02.

Synthesis of 1-bromo-3-methylsulfonyl-5-(2,2,2-trifluoroethoxy)benzene(R57)

Step 1: Synthesis of Intermediate I-26.1

3-bromo-5-methylsulfanyl-phenol (5 g, 22.82 mmol) is dissolved indichlormethane (100 mL) and cooled down to 0° C. 3-chloroperbenzoic acid(10.23 g, 45.64 mmol) is added and stirred at r.t. overnight. Thereaction mixture is diluted with dichlormethane and water. The organiclayer is separated, dried and concentrated. The crude product ispurified by reversed phase HPLC and freeze dried.

Yield 55%, m/z 251/253 [M+H]+, rt 0.47 min, LC-MS Method X018_S01.

Step 2: Synthesis R57

To I-26.1 (150 mg, 0.597 mmol) and potassium carbonate (206.41 mg, 1.49mmol) in DMF is added 1,1,1-trifluoro-2-iodo-ethane (147.196 μL, 1.493mmol) and stirred over 3 days at 85° C. The reaction mixture is dilutedwith water, the precipitate is filtered off, washed with water anddried. Yield 52%, m/z 350/352 [M+H]+, rt 1.16 min, LC-MS MethodV011_S01.

The following intermediates as shown in Table 54 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 54 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method elabR57.1

332/334 [M + NH₄]+ 1.01 V011_S01 LG1SLA00459 R57.2

296/298 [M + NH₄]+ 1.11 V011_S01 LG1SLA00495

The two intermediates in the table above are purified by reversed phaseHPLC.

Synthesis of 4-bromo-N1-methyl-benzene-1,2-diamine (R58)

Step 1: Synthesis of Intermediate I-36.1

To 4-bromo-2-nitro-aniline (10 g, 46.08 mmol) in DMF (200 mL) are addedpotassium carbonate is (15 g, 108.53 mmol) and portionwise methylaminehydrochloride (3.11 g, 46.08 mmol) and stirred overnight at r.t. Thereaction mixture is filtered and concentrated. The crude product istriturated with DIPE, filtered off and dried. Yield 86%

Step 2: Synthesis of R58

To I-36.1 (5.27 g, 22.81 mmol) in ethyl acetate is added platinum oncarbon (550 mg) and stirred under hydrogen (5 bar) at r.t. for 4 h. Thereaction mixture is filtered through a pad of celite and concentrated.The crude product is used without further purification for the next step

Yield 96%

Synthesis of 5-bromo-N,1-dimethyl-benzimidazol-2-amine (R60)

Step 1: Synthesis of Intermediate I-27.1

4-bromo-1-n-methylbenzene-1,2-diamine (4.42 g, 21.98 mmol),N,N′-carbonyl-di-(1,2,3-triazole (4.178 g, 24.18 mmol), and TEA (9.184mL, 65.95 mmol) in THF (70 mL) are stirred at r.t. for 30 min, thenheated under reflux overnight. The reaction mixture is concentrated,triturated with water, filtered off and dried. The residue is trituratedagain with DIPE and filtered off.

Yield 88%

Step 2: Synthesis of Intermediate I-27.2

I-27.1 (4.41 g, 19.42 mmol) and phosphoroxybromide (27.84 g, 97.11 mmol)are stirred at 100° C. for 3 h. The reaction mixture is diluted withiced water. The precipitate is filtered off and triturated with DIPE.

Yield 89%

Step 3: Synthesis of R60

I-27.2 (200 mg, 0.69 mmol) and methylamine in methanol 2 mol/L (2 mL, 4mmol) are stirred at 80° C. for 16 h. The reaction mixture is purifiedby reversed phase HPLC.

Yield 63%, m/z 240/242 [M+H]+, rt 0.48 min, LC-MS Method X011_S03.

Synthesis of(7R,8aR)-7-methoxy-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine(R63)

Step 1: Synthesis of Intermediate I-28.1

To 2-(tert-butoxycarbonylamino)acetic acid (1.5 g, 8.56 mmol) and HATU(3.58 g, 9.42 mmol) in DMF (15 mL) is added DIPEA (5.89 mL, 34.25 mmol)and stirred for 15 min. Methyl(2R,4R)-4-methoxypyrrolidine-2-carboxylate hydrochloride (1.675 g, 8.56mmol) is added and stirred at r.t. overnight. The reaction mixture isdiluted with dichlormethan and NaHCO₃-solution. The organic layer isseparated and washed with brine, dried and concentrated. The cruderesidue is purified by reversed phase HPLC.

Yield 74%, m/z 317 [M+H]+, rt 0.47 min, LC-MS Method X018_S01.

Step 2: Synthesis of Intermediate I-28.2

I-28.1 (2 g, 6.32 mmol), hydrochloric acid in dioxane 4 mol/L (10 mL, 40mmol) and dioxane (30 mL) are stirred at r.t. overnight. The reactionmixture is directly used for the next step.

Step 3: Synthesis of Intermediate I-28.3

To the reaction mixture from the previous step is added TEA till a pHvalue of 8 is reached. The precipitate is filtered off and the motherliquor is concentrated to isolate the desired product. Yield 97%, m/z185 [M+H]+, rt 0.18 min, LC-MS Method V011_S01.

Step 4: Synthesis of R63

To lithiumaluminium hydride 1 mol/L in THF (12.215 mL, 12.215 mmol) inTHF (8 mL) is added a solution of I-28.3 (900 mg, 4.886 mmol) in THF (4mL) dropwise and stirred at r.t. for 1.5 h. Under cooling the reactionmixture is poured into aq. sodium hydroxide (1 mol/L) and diluted withTHF (30 ml). The precipitate is filtered off and the mother liquor isconcentrated. The residue is diluted to with methanol and stirred a fewminutes at 50° C. The precipitate is filtered off and the mother liquoris concentrated to give the crude product which is purified over aminophase silica gel. Yield 36%

Synthesis of 3,4,4a,5,6,7,8,8a-octahydro-2H-2,6-naphthyridin-1-one (R65)

5,6,7,8-tetrahydro-2H-2,6-naphthyridin-1-one hydrochloride (250 mg,1.339 mmol), platinum oxide (100 mg) and glacial acetic acid (10 mL) arestirred under hydrogen (5 bar) at r.t. for 24 h.

The reaction mixture is filtered off and concentrated. The crude productis purified over amino phase silica gel.

Yield 71%.

Synthesis of 4-bromo-2-isopropyl-1-methylsulfinyl-benzene (R67)

1-isopropyl-2-methylsulfanyl-benzene (400 mg, 2.41 mmol) is dissolved indichlormethane (4 mL) and cooled down to 0° C. Bromine (123.21 μL, 2.41mmol) is added and stirred at r.t. for 3 days.

The reaction mixture is concentrated and purified by reversed phaseHPLC.

Yield 53%, m/z 261/263 [M+H]+, rt 1.06 min, LC-MS Method V011_S01.

Synthesis of (3-bromophenyl)imino-dimethyl-oxo-sulfane (R70)

1-Bromo-3-iodo-benzene (250 μL, 1.96 mmol), (methylsulfonimidoyl)methane(219.188 mg, 2.353 mmol), cesium carbonate (894.466 mg, 2.745 mmol) anddioxane (12 mL) are purged with is argon.(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane(85.098, 0.147 mmol) and tris(dibenzylideneacetone)dipalladium(0) (44.89mg, 0.049 mmol) are added, purged again with argon and stirred at 105°C. for 3 h.

The reaction mixture is filtered through a pad of celite. The filtrateis concentrated and purified by reversed phase HPLC.

Yield 94%, m/z 249 [M+H]+, rt 0.74 min, LC-MS Method Z018_S04.

The following intermediate as shown in Table 55 is synthesized in asimilar fashion from the appropriate intermediates:

TABLE 55 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method elabR70.1

318 0.83 Z018_S04 CCCYUJ00250

Synthesis of 2-(4-amino-3-bromo-phenyl)-N-methyl-acetamide (R71)

To 2-(4-amino-3-bromo-phenyl)acetic acid (5 g, 21.73 mmol) in methanol(50 mL) and dichlormethane (100 mL) is added at −5° C.trimethylsilyldiazomethane in diethylether 2 mol/L (31.51 mL, 63.03mmol) dropwise over a period of 30 min. The reaction mixture is allowedto warm up to r.t. and concentrated. The crude product is used withoutfurther purification.

Yield 95%, m/z 244/246 [M+H]+, rt 0.48 min, LC-MS Method X011_S03.

Synthesis of 2-(4-amino-3-bromo-phenyl)-N-methyl-acetamide;2,2,2-trifluoroacetic acid (R72)

Step 1: Synthesis of Intermediate I-29.1

4-amino-3-bromophenylacetic acid methyl ester (22 g, 81.12 mmol),di-t-butyl-dicarbonate (20.13 g, 92.22 mmol), 4-dimethylaminopyridine(991.02 mg, 8.11 mmol) and dichlormethane (300 mL) are stirred togetherat r.t. overnight. The reaction mixture is extracted with KHSO₄-solution(10%), NaHCO₃-solution and brine. The organic layer is separated, driedand concentrated. The residue is purified over silica gel.

Yield 8%, m/z 344/346 [M+H]+, rt 1.34 min, LC-MS Method V011_S01.

Step 2: Synthesis of Intermediate I-29.2

To I-29.1 (4 g, 11.62 mmol) in dioxane (50 mL) is added a solution oflithium hydroxide (400 mg, 13.95 mmol) in water (5 mL) and stirred atr.t. overnight. The precipitate is filtered by suction and dried.

Yield 91%, m/z 274/276 [M+H−isobutene]+, rt 0.29 min, LC-MS MethodX011_S03.

Step 3: Synthesis of Intermediate I-29.3

To I-29.2 (150 mg, 0.45 mmol) in DMF (2 mL) is added TBTU (175.04 mg,0.55 mmol) and after 7 min methylamine 2 mol/L in THF (0.9 ml, 1.82mmol) is added. The reaction mixture is stirred at r.t. overnight andpurified by reversed phase HPLC.

Yield 35%, m/z n.d. [M+H]+, rt 0.55 min, LC-MS Method X011_S03.

Step 4: Synthesis of R72

To I-29.3 (97 mg, 0.28 mmol) in dichlormethane (2 mL) is addedtrifluoracetic acid (0.5 mL) and stirred at r.t. for 1 h. The reactionmixture is concentrated.

Yield 99%, m/z 243/245 [M+H]+, rt 0.26 min, LC-MS Method X012_S01.

Synthesis of 4-amino-3-fluoro-5-iodo-benzamide (R74)

Step 1: Synthesis of Intermediate I-30.1

2-fluoro-6-iodo-4-(methoxycarbonyl)aniline (30 g, 0.1 mol), ethanol (300mL) and NaOH 20% (30 mL) are stirred together under reflux for 2 h. Thereaction mixture is diluted with water and acidified with KHSO₄-solution(1 mol/L). The precipitate is filtered off and recrystallized withethanol.

Yield 86%

Step 2: Synthesis of R74

To I-30.1 (26 g, 0.092 mol) in DMF (200 mL) is added1,1′-carbonyldiimidazole (17.8 g, 0.11 mol) and ammonium carbonate (48g, 0.5 mol) and stirred at 50° C. for 30 min. The reaction mixture isconcentrated and the residue is diluted with water. The precipitate isfiltered off and recrystallized with ethanol.

Yield 83%

Synthesis of 4-amino-3-fluoro-5-iodo-benzonitrile (R74.1)

To R74 (2 g, 7.14 mmol) in dichlormethane (50 mL) is added R2 (3.4 g,14.28 mmol) and stirred at r.t. overnight. The reaction mixture isextracted with water. The organic layer is separated, dried andconcentrated. The crude residue is filtered through a pad of silica gel(eluent (ethyl acetate/cyclohexane 3:7).

Yield 53%, m/z 263 [M+H]+, rt 0.47 min, LC-MS Method X012_S01.

Synthesis of 3-tetrahydrofuran-3-yl-3,8-diazabicyclo[3.2.1]octane (R77)

Step 1: Synthesis of Intermediate I-31.1

To tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride(300 mg, 1.21 mmol) in THF (5 mL) is added tetrahydrofuran-3-one (114.21mg, 1.33 mmol) and sodium triacetoxyborhydride (349.78 mg, 1.57 mmol)and stirred at r.t. for 0.5 h.

Sodium acetate (148.40 mg, 1.81 mmol) is added and stirred at r.t.overnight.

The reaction mixture is diluted with aq. sodiumhydrogen carbonatesolution and extracted with ethyl acetate. The organic layer isseparated, dried and concentrated. The crude residue is purified byreversed phase HPLC.

Yield 61%, m/z 283 [M+H]+, rt 0.61 min, LC-MS Method V011_S01.

The following intermediates as shown in Table 56 are synthesized in ananalogous manner from the appropriate intermediates:

TABLE 56 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodI-31.1.1

213 n.d. n.d. I-31.1.2

303 1.34 V11_S01

For I-31.1.1 sodium cyanoborhydride and methanol is used instead ofsodium triacetoxyborhydride and THF.

Step 2: Synthesis of R77

I-31.1 (206 mg, 0.73 mmol) and hydrochloric acid in ether 1 mol/L (5 mL)is stirred at r.t. for 3 h. The reaction mixture is concentrated,diluted in dichlormethan/methanol 7/3 and filtered over amino phasesilica gel.

Yield 99%, m/z 183 [M+H]+, rt 0.28 min, LC-MS Method V011_S01.

The following intermediates as shown in Table 56.1 are synthesized in ananalogous manner from the appropriate intermediates:

TABLE 56.1 m/z rt LC-MS Intermediate Structure [M + H]+ (min) methodR77.1

n.d. n.d. n.d. R77.2

203 0.91 V11_S01

For R77.1 p-toluenesulfonic acid monohydrate is used for thedeprotection.

Synthesis of tert-butyl4-(5-bromo-2-oxo-indolin-1-yl)piperidine-1-carboxylate (R79)

Step 1: Synthesis of Intermediate I-38.1

To 1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one (200 mg, 0.93 mmol)in dichlormethane (5 mL) are added TEA (0.129 mL, 0.93 mmol) anddi-t-butyl-dicarbonate (201.82 mg, 0.93 mmol). The reaction mixture isstirred for 10 min, diluted with water and sodium hydrogencarbonatesolution and extracted with dichlormethane. The organic layer is driedand concentrated. Yield>95%, m/z 261 [M+H−tert.butyl]+, rt 1.055 min,LC-MS Method Z020_S01.

Step 2: Synthesis of R79

Tert-butyl 4-(2-oxoindolin-1-yl)piperidine-1-carboxylate (100 mg, 0.32mmol) in ACN is cooled down to −10° C., N-bromosuccinimide (56.47 mg,0.32 mmol) is added and stirred at −10° C. for 2 h. The reaction mixtureis diluted with dichlormethane and water. The organic layer isseparated, dried and concentrated. The crude product is used for thenext step without further purification. Yield 99%, m/z 395 [M+H]+, rt1.126 min, LC-MS Method Z020_S01.

Synthesis of 2-amino-N-cyclopropyl-3-iodo-benzamide (R82)

Synthesis of R82

To 2-amino-3-iodo-benzoic acid (200 mg, 0.76 mmol) in DMF (1 mL) TBTU(244.15 mg, 0.76 mmol) and DIPEA (245.69 μL, 1.52 mmol) are added andstirred at r.t. for 7 min. Cyclopropylamine (52.69 μL, 0.76 mmol) isadded and stirred at r.t. overnight. The reaction mixture is dilutedwith water and the precipitate is filtered off and dried.

Yield 89%, m/z 303 [M+H]+, rt 0.49 min, LC-MS Method X012_S01.

Synthesis of 6-bromo-1-(1-methyl-4-piperidyl)indolin-2-one (R85)

Step 1: Synthesis of Intermediate I-32.1

To sodium hydride 60% (1.536 g, 38.4 mmol) in DMSO (30 mL) undernitrogen atmosphere is added di-tert.butylmalonate (8.61 mL, 38.4 mmol)dropwise. The reaction mixture is stirred at 100° C. for 1 h, cooleddown to 10° C. and a solution of 2,5-dibromonitrobenzene (4.93 g, 17.55mmol) in DMSO (25 mL) is added dropwise. After the addition the reactionmixture is stirred at 100° C. for 1 h again.

The reaction mixture is poured into ammoniumchloride solution and the pHis adjusted with to sodium hydrogensulfate to pH 7. Water and a mixtureof ethylycetate/cyclohexane 1/1 is added. The aq. layer is extractedwith this mixture. The organic layer is separated, washed with brine,dried and concentrated. The crude product is used for the next stepwithout further purification. Yield 45%, m/z 414/416 [M+H]+, rt 1.215min, LC-MS Method Z011_S03.

Step 2: Synthesis of Intermediate I-32.2

To I-32.1 (1 g, 2.4 mmol) in ethanol is added platinum on carbon (50 mg)and stirred under hydrogen (50 psi) at r.t. for 67 h. The reactionmixture is filtered and concentrated. The crude residue is purified byreversed phase HPLC.

Yield 34%, m/z 274/276 [M+H]+, rt 1.156 min, LC-MS Method Z011_S03.

Step 3: Synthesis of Intermediate I-32.3

To I-32.2 (316.66 mg, 0.81 mmol) in dichlormethane (2 mL) and glacialacetic acid (73.88 mL, 1.22 mmol) are added Boc-4-piperidone (210.41 mg,1.06 mmol), titanium (IV)isopropoxide (346.17 mg, 1.22 mmol) and sodiumtriacetoxyborhydride (258.14 mg, 1.22 mmol) and stirred at 50° C. for 3h and at r.t. over 3 days. The reaction mixture is diluted withdichlormethane and water. The organic layer is separated andconcentrated. The crude product is purified by reversed phase HPLC.Yield 27%, m/z 569/571 [M+H]+, rt 1.049 min, LC-MS Method Z011_U03.

Step 4: Synthesis of Intermediate I-32.4

To I-32.3 (125.3 mg, 0.2 mmol) in toluene (1 mL) is added4-ethyl-benzenesulfonic acid (163.9 mg, 0.9 mmol) and stirred at 140° C.by microwave irridation. The reaction mixture is concentrated anddiluted with sodium hydroxide 1 mol/L and dichlormethane andconcentrated again. The crude product is used without furtherpurification for the next step.

Yield 92%, m/z 295/7 [M+H]+, rt 0.867 min, LC-MS Method Z011_S03.

Step 5: Synthesis of R85

To I-32.4 (60 mg, 0.20 mmol) in methanol (1 mL) are added formaldehydein water (37%) (75.67 μL, 1.02 mmol) and glacial acetic acid (17.44 μL,0.31 mmol), stirred at r.t. for 75 min, afterwards sodiumtriacetoxyborhydride (107.70 mg, 0.51 mmol) is added. The reactionmixture is stirred at r.t. overnight.

The reaction mixture is diluted with sodium hydroxide 1 mol/L anddichlormethane. The organic layer is separated, washed with brine, driedand concentrated. The crude product is used for the next step withoutfurther purification.

Yield 52%, m/z 309/311 [M+H]+, rt 0.912 min, LC-MS Method Z011_S03.

Synthesis of 6-bromo-N-methyl-1H-benzimidazol-2-amine (R88)

Step 1: Synthesis of Intermediate I-33.1

To 4-bromobenzene-1,2-diamine (0.5 g, 3 mmol) in dichlormethane (10 mL)and DIPEA (0.55 mL, 3 mmol) is added methylimino(thioxo)methane (0.2 g,3 mmol) and stirred at 50° C. for 4 h and at r.t. overnight. Thereaction mixture is extracted with, aq. acetic acid (1%), aq. sodiumcarbonate (10%) and brine. The organic layer is separated, dried andconcentrated. The residue is purified over silica gel.

Yield 69%, m/z 260/262 [M+H]+, rt 0.45 min, LC-MS Method X018_S02.

Step 2: Synthesis of R88

To I-33.1 (130 mg, 0.50 mmol) in ACN (2.5 mL) are addedbenzotriazol-1-yl-oxy-tris(dimethylamino) phosphoniumhexafluorophosphate (BOP reagent) (330 mg, 0.50 mmol) and DBU (150 μL,1.00 mmol) and stirred at r.t. for 0.5 h. The reaction mixture ispurified by reversed phase HPLC.

Yield 51%

Synthesis of 4-(6-bromo-5-fluoro-tetralin-2-yl)morpholine (R91)

To 6-bromo-5-fluoro-tetralin-2-one (1 g, 4.11 mmol) and morpholine (0.36mL, 4.11 mmol) in dichlormethane is added glacial acetic acid (0.52 mL,9.05 mmol). The reaction mixture is cooled with an ice bath and sodiumtriacetoxyborhydride (1.74 g, 8.23 mmol) is added. The reaction mixtureis stirred at r.t. overnight. Morpholine (0.2 mL) is added and stirredagain at r.t. overnight. The reaction mixture is basified with potassiumcarbonate solution (20%) and stirred for 15 min. The organic layer isseparated and the aq. layer is washed two times with dichlormethane. Theorganic layers are dried and concentrated. The crude product is purifiedby reversed phase HPLC Yield 57%, m/z 314/316 [M+H]+, rt 0.68 min, LC-MSMethod X011_S03.

The following intermediate as shown in Table 57 is synthesized in asimilar fashion from the appropriate intermediates:

TABLE 57 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method R91.1

172 n.d. n.d.

Synthesis of 1-tetrahydrofuran-3-ylpiperidin-4-one (R91.2)

To R91.1 1-tetrahydrofuran-3-ylpiperidin-4-ol (200 mg, 1.17 mmol) indichlormethane (5 mL) is added dess-martin periodine (595 mg, 1.40 mmol)and stirred at r.t. for 5 h. The reaction mixture is filtered throughALOX/N and washed with cyclohexane/ethyl acetate 1:3. The filtrate isconcentrated.

Yield 51%

Synthesis of(4aS,7aR)-2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazine

Step 1: Synthesis of Intermediate I-34.1

To tert-butyl(4aS,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxylate(200 mg, 0.88 mmol) in methanol (3 mL) are added formaldehyde in water(37%) (26.44 mg, 0.33 mmol) and glacial acetic acid (79.71 mg, 1.31mmol), stirred at r.t. for 75 min, afterwards sodiumtriacetoxyborhydride (464.19 mg, 2.19 mmol) is added. The reactionmixture is stirred at r.t. for 2 h Additional formaldehyde in water(37%) (26.44 mg, 0.33 mmol) is added and stirred in a 50° C. warm waterbath for 10 min, sodium triacetoxyborhydride (464.19 mg, 2.19 mmol) isadded and stirred at r.t. for 1.5 h. The reaction mixture is dilutedwith aq. sodium hydrogencarbonate solution and water and extracted withethyl acetate. The organic layer is washed with aq. sodiumhydrogencarbonate solution and brine, dried and concentrated. Yield 79

The following intermediates as shown in Table 58 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 58 m/z rt Intermediate Structure [M + H]+ (min) LC-MS methodI-34.1.1

n.d. n.d. n.d. I-34.1.2

n.d. n.d. n.d.

Step 2: Synthesis of R93

To I-34.1 (167 mg, 0.69 mmol) in dichlormethan (3 mL) p-toluenesulfonicacid monohydrate (655.48 mg, 3.45 mmol) is added and stirred at r.t.overnight. The reaction mixture is extracted with sodium hydroxide 1mol/L. The organic layer is separated dried and concentrated. Due toless yield the aq. layer is saturated with sodium chloride and extractedwith dichlormethane. The aq layer is concentrated and extracted againwith dichlormethane. All organic layers are combine, dried andconcentrated. Yield 76%

The following intermediates as shown in Table 59 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 59 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodR93.1

n.d. n.d. n.d. R93.2

n.d. n.d. n.d.

Synthesis of 1-bromo-4-(bromomethyl)-2,5-difluoro-benzene (R99)

R98 (31.4 g, 15.17 mmol), N-bromosuccinimide (32.4 g, 1.6 mmol), AIBN(4.98 g, 30.34 mmol) in tetrachloromethane is heated at 90° C.overnight. The reaction mixture is cooled down to r.t. and concentrated.The residue is dissolved in ethyl acetate and extracted with water. Theorganic layer to is dried over MgSO₄, filtered and concentrated. Thecrude product is purified by high vacuum distillation (boiling point 95°C.-98° C. by oil bath temperature of 140° C.)

Yield 67%

The following intermediate as shown in Table 60 is synthesized in ananalogous manner from the appropriate intermediates:

TABLE 60 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodR99.1

n.d. 0.65 X012_S01

For R99.1 the reaction temperature is 80° C. For the work up thereaction mixture is cooled to r.t. and the precipitate filtered off. Themother liquor is extracted with aq. hydrochloric acid (1 mol/L) and aq.sodium hydroxide (1 mol/L), dried and concentrated. The crude product isused without further purification.

Synthesis of 2-benzyloxy-4-bromo-1-(chloromethyl)benzene (R100)

Step 1: Synthesis of Intermediate I-35.1

To methyl 4-bromo-2-hydroxy-benzoate (4.3 g, 18.61 mmol) in acetonitrile(50 mL) are added bromomethylbenzene (2.23 mL, 19.54 mmol) and potassiumcarbonate (3.86 g, 27.92 mmol) and stirred for 4 h at reflux. Thereaction mixture is cooled down to r.t., diluted with water andextracted with ethyl acetate. The organic layer is separated, dried overMgSO₄ and concentrated. The crude is residue is purified over silica gel(eluent: cyclohexane/ethyl acetate 95:5). Yield 75%

Step 2: Synthesis of Intermediate I-35.2

I-35.1 (4.5 g, 14.01 mmol) is dissolved in THF (50 mL) and a solution oflithium aluminium hydride in THF (8.41 mL, 8.41 mmol) is added dropwisebetween 5° C.-10° C. The reaction mixture is stirred 1 h under coolingand 1.5 h at r.t. Afterwards the mixture is cooled down and hydrolysedwith 30 mL aq. hydrodchloric acid (1 mol/L), diluted with water andextracted with ethyl acetate. The organic layer is washed with water,dried over MgSO₄ and concentrated. The crude residue is used for thenext step without further purification. Yield 94%

Step 3: Synthesis of R100

To I-35.2 (3.85 g, 13.13 mmol) in dichlormethane (40 mL) is addedtriethylamine (2.21 mL, 15.76 mmol) and cooled down to 0° C.-2° C.Methanesulfonyl chloride (1.12 mL, 14.45 mmol) dissolved indichlormethane (3 mL) is added dropwise. The reaction mixture is stirredfor 1 h at 2° C.-5° C. and overnight at r.t. The reaction mixture isconcentrated, diluted with dichlormethane and water. The organic layeris washed with 1 mol/L hydrochloric acid, water, dried over MgSO₄ andconcentrated. The crude residue is used for the next step withoutfurther purification. Yield 74%

Synthesis of tert-butyl N-(4-amino-3-bromo-phenyl)carbamate (R104)

To tert-butyl N-(3-bromo-4-nitro-phenyl)carbamate (1 g, 3.15 mmol) inethyl acetate (20 mL) is added tin (II) chloride dihydrate (3.56 g,15.77 mmol) and stirred overnight at r.t. The reaction mixture isbasified with potassium carbonate/sodium hydroxide. The organic layer isseparated, dried and concentrated. The crude product is used withoutfurther purification for the next step. Yield 83%, m/z 287/289[M+H]+, rt0.58 min, LC-MS Method X011_S03.

The following intermediate as shown in Table 61 is synthesized in ananalogous manner from the appropriate intermediates:

TABLE 61 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodR104.1

197/199 0.45 X012_S01

Synthesis of 3,4,6,7,9,9a-hexahydro-1H-pyrido[2,1-c][1,4]oxazin-8-one(R106)

Step 1: Synthesis of Intermediate I-37.1

To methyl 2-morpholin-3-ylacetate hydrochloride (1 g, 5.11 mmol) inmethanol (25 mL) are added TEA (0.785 mL, 5.63 mmol) and acrylic acidmethyl ester (0.465 mL, 5.16 mmol) and stirred overnight at r.t. Againacrylic acid methyl ester (0.465 mL, 5.16 mmol) is added and stirred 3days at r.t. The reaction mixture is concentrated and the crude productis purified over silica gel (eluent: ethyl acetate).

Yield 93%, m/z 246[M+H]+, rt 0.77 min, LC-MS Method V011_S01.

Step 2: Synthesis of Intermediate I-37.2

Under argon atmosphere I-37.1 (1.09 g, 4.44 mmol) is dissolved in THF(40 mL) and cooled down is to −70° C. Lithium bis(trimethylsilyl)amide 1mol/L (9 mL, 9 mmol) is added dropwise and stirred for 4 h at −70° C.The reaction mixture is quenched with hydrochloric acid 1 mol/L (15 mL).Afterwards solid sodium carbonate (1 g) is added. The aq. layer isextracted with ethyl acetate. The organic layers are combined, dried andconcentrated. The crude product is purified over silica gel (eluent:ethyl acetate). Yield 68%

Step 3: Synthesis of R106

I-37.2 (0.63 g, 2.96 mmol) and hydrochloric acid 4 mol/L (15 mL) arestirred at 100° C. overnight. The reaction mixture is diluted with waterand freeze-dried. The crude product is filtered over amino phase silicagel (eluent: dichlormethane/methanol). Yield 82%

Synthesis of 5-bromo-2-methylsulfonyl-phenol (R109)

To 4-bromo-2-fluoro-1-methylsulfonyl-benzene (2 g, 7.9 mmol) in DMF (15mL) is added 2-methanesulfonyl-ethanol (1.47 g, 11.85 mmol). Sodiumhydride (948.16 mg, 23.71 mmol) is added in portions at 0° C. Thereaction mixture is allowed to come to r.t. and is added dropwise intocooled aq. hydrochloric acid. The aq. layer is extracted with ethylacetate. The organic layer is dried over MgSO₄, filtered andconcentrated. The crude residue is purified by reversed phase HPLC.Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_S01.

Examples

(rt=retention time) Deprotection Methods: TSA (toluene sulfonic acid cf.Example 1), SI (trimethylsilyl iodide cf. example 2 or 3), FA (formicacid cf. example 4 or 7), TFA (trifluoroacetic acid). Stereochemistry atthe carbon atom adjacent to the nitrile group is assigned: Stereo bondis means S-isomer, non-stereo bond means 1:1 mixture of stereoisomers.

TABLE 62 Syn./ Deprot. Yield Example Structure Educt Method [%] 1

I-1.5 A/TSA 47 2

I-2.3 A1/SI 44 3

I-3.3 A2.1/SI 62 4

I-4.3 A3/FA 86 5

I-5.2 A4/FA 34 6

I-6.2 A5/TSA 86 7

I-7.3 B/FA 39 8

I-8.2 C/SI 19 9

I-9.1 D/SI 32 10

I-3.3.1 A2.1/SI 25 11

I-3.2.2 A2.1/SI 17 12

I-2.3.1 A1/FA 36 13

I-2.3.7.1 A1/FA 56 14

I-4.3.1 A3/SI 43 15

I-4.3.2 A3/SI 21 16

I-4.3.3 A3/TSA 93 17

I-2.3.2 A1/TSA 16 18

I-2.3.3 A1/TSA 36 19

I-4.3.1 A3/SI 59 20

I-2.3.7.3 A1/TSA 22 21

I-2.3.7.4 A1/FA 49 22

I-4.3.5 A3/SI 70 23

I-2.3.4 A1/TSA 37 24

I-2.3.74.1 A1/TFA 45 25

I-4.3.6 A3/TSA 45 26

I-2.3.5 A1/TSA 49 27

I-2.3.6 A1/TSA 38 28

I-2.3.7.5 A1/FA 75 29

I-4.3.7 A3/SI 40 30

I-2.3.8 A1/TSA 46 31

I-4.3.8 A3/SI 39 32

I-3.2.4 A2.2/TSA 31 33

I-2.3.9 A1/TSA 16 34

I-3.3.3 A2.1/SI 32 35

I-4.3.9 A3/SI 77 36

I-2.3.10 A1/TSA 39 37

I-4.3.10 A3/FA 98 38

I-2.3.11 A1/TSA 6 39

I-2.3.12 A1/TSA 30 40

I-2.3.13 A1/TSA 49 41

I-4.3.11 A3/FA >95 42

I-3.2.6 A2.1/TSA 75 43

I-3.2.7 A2.2/TSA 84 44

I-2.3.7.6 A1/FA 64 45

I-4.3.12 A3/SI 58 46

I-2.3.14 A1/TSA 12 47

I-5.2 A4/TSA 57 48

I-2.3.7.7 A1/FA 20 49

I-4.3.13 A3/FA 93 50

I-2.3.15 A1/TFA 31 51

I-4.3.14 A3/FA 76 52

I-4.3.4 A3/SI 33 53

I-4.3.16 A3/FA 85 54

I-4.3.17 A3/FA 96 55

I-2.3.7.8 A1/FA 71 56

I-4.3.18 A3/FA 67 57

I-2.3.16 A1/TSA 38 58

I-7.3 B/FA 90 59

I-2.3.17 A1/FA 37 60

I-2.3.18 A1/TSA 33 61

I-4.3.15 A3/SI 47 62

I-4.3.20 A3/FA 91 63

I-2.3.19 A1/TSA 19 64

I-2.3.20 A1/TSA 48 65

I-2.3.21 A1/TSA 6 66

I-5.2 A4/TSA 23 67

I-5.2 A4/TSA 53 68

I-2.3.22 A1/TSA 17 69

I-2.3.23 A1/TSA 19 70

I-2.3.24 A1/TSA 58 71

I-4.3.21 A3/FA >95 72

I-2.3.25 A1/TSA 13 73

I-2.3.26 A1/TSA 53 74

I-2.3.7.9 A1/TSA 41 75

I-3.3.4 A2.1/SI 4 76

I-4.3.22 A3/FA 89 77

I-5.2 A4/TSA 40 78

I-2.3.27 A1/TSA 7 79

I-4.3.23 A3/FA 80 80

I-2.3.28 A1/TSA 24 81

I-4.3.24 A3/SI 31 82

I-5.2 A4/TSA 44 83

I-4.3.25 A3/FA >95 84

I-5.2 A4/TSA 46 85

I-2.3.29 A1/FA 60 86

I-2.3.30 A1/FA 63 87

I-2.3.7.10 A1/TSA 8 88

I-4.3.26 A3/FA 52 89

I-5.2 A4/TSA 48 90

I-5.2 A4/TSA 77 91

I-3.2.9 A2.2/TSA 92 92

I-2.3.31 A1/TSA 14 93

I-2.3.32 A1/TSA 54 94

I-5.2 A4/TSA 80 95

I-3.2.10 A2.1/TSA 53 96

I-2.3.33 A1/FA 87 97

I-2.3.34 A1/TSA 22 98

I-3.2.11 A2.1/SI 83 99

I-5.2 A4/TSA 34 100

I-2.3.35 A1/TSA 16 101

I-5.2 A4/TSA 48 102

I-3.2.12 A2.1/SI 29 103

I-2.3.36 A1/TSA 17 104

I-2.3.37 A1/TSA 8 105

I-5.2 A4/TSA/TSA 26 106

I-5.2 A4/TSA 30 107

I-4.3.27 A3/FA 80 108

I-3.2.13 A2.1/SI 42 109

I-5.2 A4/TSA 41 110

I-2.3.38 A1/TSA 21 111

I-5.2 A4/TSA 84 112

I-5.2 A4/TSA 22 113

I-2.3.39 A1/TSA 45 114

I-2.3.40 A1/TSA 53 115

I-2.3.41 A1/TSA 30 116

I-2.3.42 A1/TSA 8 117

I-2.3.43.1 A1/SI 57 118

I-2.3.44 A1/TSA 40 119

I-5.2 A4/TSA 37 120

I-4.3.19 A3/SI 5 121

I-2.3.45 A1/TSA 41 122

I-4.3.19 A3/SI 27 123

I-10.5 E/FA 10 124

I-5.2 A4/TSA 36 125

I-4.3.28 A3/TSA 79 126

I-2.3.46 A1/TSA 7 127

I-8.2.1 C/SI 36 128

I-10.5 E/FA 5 129

I-2.3.47 A1/TSA 21 130

I-2.3.48 A1/TSA 33 131

I-2.3.49 A1/TSA 28 132

I-2.3.50 A1/TSA 36 133

I-2.3.51 A1/TSA 28 134

I-2.3.52 A1/TSA 8 135

I-2.3.53 A1/TSA 25 136

I-2.3.54 A1/TSA 33 137

I-2.3.55 A1/TSA 25 138

I-2.3.56 A1/TSA 41 139

I-2.3.57 A1/TSA 26 140

I-2.3.58 A1/TSA 16 141

I-2.3.59 A1/TSA 28 142

I-2.3.60 A1/TSA 24 143

I-2.3.61 A1/TSA 33 144

I-2.3.62 A1/TSA 34 145

I-2.3.63 A1/TSA 21 146

I-2.3.64 A1/TSA 32 147

I-2.3.65 A1/TSA 34 148

I-2.3.66 A1/TSA 10 149

I-2.3.67 A1/TSA 23 150

I-2.3.68 A1/TSA 33 151

I-2.3.69 A1/TSA 25 152

I-2.3.70 A1/FA 68 153

I-2.3.71 A1/FA 73 154

I-3.2.14 A2.2/TSA 59 155

I-3.3.5 A2.1/SI 62 156

I-3.3.6 A2.1/SI 25 157

I-4.3.32 A3/FA 36 158

I-2.3.72 A1/SI 57 159

I-1.5.1 A/TSA 65 160

I-3.2.37 A2.1/TSA 34 161

I-4.3.33 A3/FA 75 162

I-3.2.47 A2.1/TSA 52 163

I-3.2.36 A2.1/TSA 40 164

I-4.3.34 A3/FA 78 165

I-4.3.35 A3/FA 90 166

I-3.3.7 A2.1/SI 33 167

I-3.2.46 A2.1/TSA 49 168

I-3.2.42 A2.1/TSA 37 169

I-1.5.2 A/TSA 79 170

I-4.3.36 A3/FA 77 171

I-3.2.39 A2.1/TSA 37 172

I-3.2.38 A2.1/TSA 36 173

I-3.2.45 A2.1/TSA 34 174

I-3.2.40 A2.1/TSA 33 175

I-3.2.50 A2.1/TSA 44 176

I-2.3.75.1 A1/FA 53 177

I-3.2.51 A2.1/SI 59 178

I-3.2.19 A2.2/TSA 81 179

I-3.2.49 A2.1/TSA 35 180

I-3.2.20 A2.2/TSA 56 181

I-2.3.76.1 A1/FA 31 182

I-3.2.22 A2.2/TSA 31 183

I-2.3.78.1 A1/FA 36 184

I-4.3.37 A3/TFA 51 185

I-4.3.38 A3/TFA 28 186

I-4.3.39 A3/TFA 40 187

I-3.2.24 A2.2/SI 17 188

I-3.2.25 A2.2/TSA 85 189

I-3.2.26 A2.2/TSA 13 190

I-3.2.27 A2.2.TSA 19 191

I-3.2.28 A2.2/TSA 84 192

I-3.2.29 A2.2/TSA 75 193

I-3.2.30 A2.2/TSA 42 194

I-3.2.41 A2.1/TSA 33 195

I-3.2.31 A2.2/TSA 86 196

I-3.2.32 A2.2/TSA 18 197

I-3.2.33 A2.2/TSA 68 198

I-3.2.48 A2.1/TSA 32 199

I-2.3.73 A1/SI 56 200

I-4.3.40 A3/TFA 51 201

I-2.3.43.2.1 A2/SI 65 202

I-4.3.41 A3/TFA 52 203

I-7.3.3 B/SI 56 204

I-3.2.34 A2.2/TSA 90 205

I-3.2.35 A2.2/TSA 76 206

I-9.1.1 D/SI 39 207

I-10.4.1 E/TFA 28 208

I-3.2.43 A2.1/TSA 22 209

I-7.3.4 B/SI 55 210

I-4.3.42 A3/TFA 46 211

I-4.3.43 A3/TFA 48 212

I-7.3.5 B/SI 54 213

I-7.3.6 B/SI 65 214

I-1.5.3 A/TSA 72 215

I-10.4.1 E/TFA 23 216

I-4.3.44 A3/TFA 38 217

I-3.2.52 A2.1/SI 64 218

I-2.3.77.1 A1/FA 24 219

I-2.3.43.3 A1/SI 41 220

I-8.2.2 C/SI 69 221

I-3.2.44 A2.1/TSA 17 222

I-3.2.53 A2.1/FA 59 223

I-2.3.43 A1/SI 60 224

I-2.3.79 A1/SI 47 225

I-4.3.45 A3/FA 15 226

I-4.3.46 A3/FA 53 227

I -4.3.47 A3/FA 28 228

I-4.3.48 A3/FA 37 229

I-4.3.49 A3/FA 14 230

I-4.3.50 A3/FA 47 231

I-4.3.51 A3/FA 30 232

I-4.3.52 A3/FA 60 233

I-4.3.53 A3/FA 37 234

I-4.3.54 A3/FA 71 235

I-4.3.55 A3/FA 38 236

I-4.3.56 A1/FA 41 237

I-4.3.57 A1/TSA 67 238

I-4.3.58 A1/FA 42 239

I-4.3.59 A1/FA 53 240

I-4.3.60 A1/FA 33 241

I-4.3.61 A1/FA 41 242

I-4.3.62 A1/FA 52 243

I-2.3.7.11 A1/FA 62 244

I-4.3.63 A1/FA 43 245

I-4.3.64 A1/FA 42 246

I-3.2.54 A2.1/SI 63 247

I-3.2.92 A2.2/TSA 20 248

I-3.2.93 A2.2/TSA 78 249

I-3.2.7 A2.2/TSA 6 250

I-3.2.7 A2.2/TSA 7 251

I-3.2.55 A2.1/TSA 65 252

I-3.2.56 A2.1/TSA 82 253

I-3.2.57 A2.1/TSA 73 254

I-3.2.58 A2.1/TSA 53 255

I-3.2.59 A2.1/TSA 58 256

I-3.2.60 A2.1/TSA 52 257

I-3.2.61 A2.1/TSA 41 258

I-3.2.62 A2.1/TSA 19 259

I-3.2.63 A2.1/FA 19 260

I-3.2.64.1 A2.1/FA 91 261

I-3.2.64.2 A2.1/FA 79 262

I-2.3.7.4.1 A1/FA 53 263

I-3.2.65 A2.1/FA 52 264

I-3.2.66 A2.1/FA 23 265

I-3.2.94 A2.2/TSA 14 266

I-3.2.95 A2.2/TSA 8 267

I-3.2.96 A2.2/TSA 41 268

I-3.2.97 A2.2/TSA 80 269

I-3.2.98 A2.2/TSA 27 270

I-3.2.99 A2.2/TSA 81 271

I-3.2.100 A2.2/TSA 17 272

I-3.2.101 A2.2/TSA 27 273

I-3.2.67 A2.1/TSA 7 274

I-3.2.68 A2.1/TSA 73 275

I-3.2.69 A2.1/TSA 71 276

I-3.2.70 A2.1/TSA 72 277

I-3.2.71 A2.1/TSA 2 278

I-3.2.72 A2.1/TSA 13 279

I-3.2.73 A2.1/TSA 28 280

I-3.3.8 A2.1/SI 90 281

I-3.3.9 A2.1/TSA 83 282

I-3.3.10 A2.1/TSA 42 283

I-3.3.11 A2.1/TSA 91 284

I-3.3.12 A2.1/TSA 80 285

I-3.2.117 A2.2/TSA 81 286

I-3.2.120 A2.2/TSA 80 287

I-3.2.121 A2.2/TSA 77 288

I-4.3.65 A3/FA 68 289

I-4.3.66 A3/FA 66 290

I-8.2.3 C/TSA 93 291

I-18.2.3 D1/MSA 18 292

I-18.2.1 D1/SI 11 293

I-18.2.2 D1/SI 24 294

I-18.2.4 D1/SI 20 295

I-18.2.5 D1/SI 13 296

I-18.2.6 D1/TSA 7 297

I-18.2.7 D1/SI 43 298

I-18.2.8 D1/SI 71 299

I-18.2.9 D1/SI 55 300

I-18.2.10 D1/TSA 24 301

I-18.2.11 D1/SI 27 302

I-18.2.12 D1/SI 58 303

I-18.2.13 D1/TSA 29 304

I-18.2.14 D1/SI 32 305

I-18.2 D1/MSA 14 306

I-18.2.15 D1/MSA 29 307

I-18.2.16 D1/SI 36 308

I-18.2.17 D1/SI 37 309

I-18.2.18 D1/MSA 11 310

I-18.2.19 D1/SI 63 311

I-18.2.20 D1/SI 13 312

I-18.2.21 D1/SI 28 313

I-18.2.22 D1/SI 7 314

I-18.2.23 D1/MSA 25 315

I-21.3 Z/TSA 60 316

I-21.3.1 Z/TSA 51 317

I-3.2.77 A2.1/TSA 47 318

I-3.2.102 A2.2/TSA 83 319

I-19.1 W/SI 34 320

I-3.3.13 A2.1/SI 74 321

I-8.2.4 C/TSA 91 322

I-18.2.24 D1/TSA 30 323

I-18.2.25 D1/TSA 32 324

I-18.2.26 D1/TSA 36 325

I-18.2.27 D1/TSA 9 326

I-18.2.28 D1/TSA 30 327

I-3.2.103 A2.2/TSA 62 328

I-3.2.104 A2.2/TSA 86 329

I-3.2.105 A2.2/TSA 62 330

I-3.2.106 A2.2/TSA 59 331

I-3.2.107 A2.2/TSA 70 332

I-3.2.79 A2.1/TSA 64 333

I-3.2.108 A2.2/TSA 33 334

I-3.2.80 A2.1/TSA 11 335

I-3.2.109 A2.2/TSA 90 336

I-3.2.110 A2.2/TSA 72 337

I-3.3.14 A2.1/TSA 86 338

I-3.3.15 A2.1/TSA 48 339

I-3.2.83 A2.1/TSA 54 340

I-3.2.84 A2.1/TSA 42 341

I-18.2.29 D1/TSA 17 342

I-3.2.85 A2.1/TSA 68 343

I-3.2.86 A2.1/TSA 35 344

I-20.1 W1/TSA 28 345

I-3.2.111 A2.2/TSA 2 346

I-3.2.87 A2.1/TSA 14 347

I-3.2.88 A2.1/TSA 18 348

I-3.3.16 A2.1/TSA 76 349

I-3.3.17 A2.1/TSA 73 350

I-3.3.18 A2.1/TSA 65 351

I-8.2.5 C/TSA 44 352

I-3.2.112 A2.2/TSA 78 353

I-3.3.19 A2.1/TSA 78 354

I-3.3.20 A2.1/TSA 62 355

I-3.2.114 A2.2/TSA 88 356

I-3.2.115 A2.2/TSA >95 357

I-3.2.116 A2.2/TSA 80 358

Ex 359 A2.1 35 359

I-3.2.136 A2.1/TSA 61

Analytical Data of Examples

TABLE 63 m/z rt Ex. [M + H]+ [min] LC-MS-Method 1 419 1.16 V011_S01 2433 0.59 X011_S01 3 420 0.41 X016_S01 4 442 0.65 Z018_S04 5 470 0.70Z018_S04 6 386 0.98 V011_S01 7 410 0.96 V018_S01 8 310 0.86 V011_S01 9387 0.39 X012_S01 10 447 0.42 X012_S01 11 420 0.41 X012_S01 12 460 0.67Z018_S04 13 426 0.63 Z018_S04 14 467 0.86 V018_S01 15 433 1.04 V001_00716 442 0.65 Z018_S04 17 428 0.81 004_CA01 18 370 0.80 004_CA01 19 4670.86 V018_S01 20 396 0.66 Z018_S04 21 438 0.64 Z018_S04 22 419 0.41Z001_002 23 410 0.78 004_CA01 24 451 0.69 Z018_S04 25 385 0.64 Z018_S0426 382 0.68 004_CA01 27 368 0.82 004_CA01 28 452 0.70 Z018_S04 29 4190.41 Z001_002 30 396 0.73 004_CA01 31 451 1.12 V011_S01 32 448 1.28V011_S01 33 438 0.93 004_CA01 34 420 1.06 V011_S01 35 407 1.10 V001_00736 370 0.80 004_CA01 37 443 0.62 Z018_S04 38 439 0.60 004_CA01 39 3820.64 004_CA01 40 407 0.72 Z018_S04 41 419 0.61 Z018_S04 42 447 1.09V011_S01 43 428 0.95 V011_S01 44 412 0.63 Z018_S04 45 421 0.90 V012_S0146 399 0.73 004_CA01 47 461 0.72 Z018_S04 48 438 0.60 X018_S01 49 4331.13 W018_S01 50 438 0.66 Z018_S04 51 457 0.64 Z018_S04 52 n.d. n.d.n.d. 53 407 0.61 Z018_S04 54 442 0.63 Z018_S04 55 493 0.64 Z018_S04 56443 0.60 Z018_S04 57 452 0.69 004_CA01 58 368 0.79 V018_S01 59 456 0.43X018_S01 60 418 0.80 004_CA01 61 451 0.88 V018_S01 62 457 0.64 Z018_S0463 382 0.64 004_CA01 64 410 0.78 004_CA01 65 382 0.64 004_CA05 66 4630.79 Z011_S03 67 395 0.82 Z011_S03 68 396 0.73 004_CA01 69 354 0.54004_CA01 70 430 0.72 Z018_S04 71 456 0.67 Z018_S04 72 412 0.76 004_CA0173 354 0.70 Z018_S04 74 466 0.70 Z018_S04 75 364 0.50 X012_S01 76 4330.65 Z018_S04 77 491 0.86 Z011_S03 78 430 0.85 004_CA01 79 419 0.62Z018_S04 80 399 0.62 004_CA01 81 449 0.90 V012_S01 82 441 0.63 Z018_S0483 407 1.09 W018_S01 84 471 0.92 Z011_S03 85 395 0.50 X018_S01 86 4600.67 Z018_S04 87 426 0.66 Z018_S04 88 442 0.64 Z018_S04 89 427 0.75Z011_S03 90 397 0.60 Z018_S04 91 450 0.98 V011_S01 92 368 0.81 004_CA0193 397 0.65 Z018_S04 94 461 0.90 Z011_S03 95 419 0.82 V012_S01 96 4310.78 Z018_S04 97 412 0.65 004_CA01 98 400 0.94 V012_S01 99 468 0.73Z011_S03 100 436 0.82 004_CA01 101 413 0.70 Z011_S03 102 400 0.92V012_S01 103 354 0.76 004_CA01 104 368 0.79 004_CA05 105 413 0.79Z011_S03 106 482 0.81 Z011_S03 107 435 1.25 W018_S01 108 400 0.82V012_S01 109 441 0.80 Z011_S03 110 382 0.67 004_CA01 111 399 0.58Z018_S04 112 443 0.75 Z011_S03 113 411 0.70 Z018_S04 114 354 0.59Z018_S04 115 414 0.68 004_CA01 116 438 0.68 004_CA01 117 385 0.65V012_S01 118 436 0.77 004_CA01 119 461 0.93 Z011_S03 120 431 0.81V018_S01 121 383 0.71 004_CA01 122 521 0.97 V018_S01 123 387 0.38X012_S01 124 427 0.83 Z011_S03 125 400 0.83 V011_S01 126 382 0.66004_CA01 127 310 0.92 V011_S01 128 387 0.35 X012_S01 129 447 0.76004_CA01 130 419 0.64 004_CA01 131 433 0.71 004_CA01 132 419 0.84004_CA01 133 440 0.83 004_CA01 134 431 0.67 004_CA01 135 430 0.74004_CA01 136 455 0.67 004_CA01 137 430 0.78 004_CA01 138 394 0.70004_CA01 139 469 0.74 004_CA01 140 469 0.73 004_CA01 141 454 0.72004_CA01 142 402 0.73 004_CA01 143 455 0.68 004_CA01 144 454 0.73004_CA01 145 411 0.78 004_CA01 146 419 0.66 004_CA01 147 431 0.64004_CA01 148 445 0.68 004_CA01 149 445 0.69 004_CA01 150 469 0.73004_CA01 151 468 0.76 004_CA01 152 460 0.67 Z018_S04 153 468 0.70Z018_S04 154 456 1.08 V011_S01 155 526 0.80 V012_S01 156 448 0.47X012_S01 157 413 0.61 Z018_S04 158 477 0.87 V012_S01 159 467 0.85V018_S01 160 382 0.64 004_CA05 161 427 0.64 Z018_S04 162 379 0.76004_CA05 163 368 0.61 004_CA05 164 455 0.71 Z018_S04 165 467 0.70Z018_S04 166 448 0.48 X12_S01 167 397 0.56 004_CA05 168 405 0.66004_CA05 169 469 1.02 V011_S01 170 441 0.67 Z018_S04 171 430 0.83004_CA05 172 415 0.87 004_CA05 173 411 0.78 004_CA05 174 405 0.63004_CA05 175 412 0.74 004_CA05 176 460 0.67 Z18_S04 177 511 1.05V012_S01 178 444 1.10 V011_S01 179 442 0.86 004_CA05 180 354 0.36X018_S01 181 437 0.65 Z018_S04 182 430 0.26 X018_S01 183 485 0.67Z018_S04 184 435 0.67 Z018_S04 185 490 0.55 Z018_S04 186 421 0.63Z018_S04 187 412 0.26 X018_S01 188 400 1.10 V011_S01 189 416 0.88V011_S01 190 416 0.89 V011_S01 191 458 1.14 V011_S01 192 400 1.10V011_S01 193 456 1.00 V011_S01 194 405 0.55 004_CA05 195 399 1.42V011_S01 196 414 0.65 V018_S01 197 371 1.28 V011_S01 198 442 0.84004_CA05 199 461 1.24 V012_S01 200 491 0.67 Z018_S04 201 399 0.32X012_S02 202 477 0.66 Z018_S04 203 359 0.46 X12_S01 204 372 0.93V011_S01 205 373 1.05 V011_S01 206 401 0.43 X12_S01 207 405 0.41 X12_S01208 382 0.60 004_CA05 209 372 0.52 X12_S01 210 475 0.74 Z018_S04 211 4350.67 Z018_S04 212 360 0.48 X12_S01 213 359 0.43 X12_S01 214 467 1.02V011_S01 215 405 0.37 X12_S01 216 461 0.70 Z018_S04 217 513 0.92V012_S01 218 470 0.69 Z018_S04 219 461 0.82 V012_S01 220 320 0.39001_CA07 221 394 0.59 004_CA05 222 466 0.65 Z018_S04 223 383 0.31X012_S02 224 526 0.36 X012_S01 225 496 0.54 Z018_S04 226 519 1.17Z018_S04 227 524 0.56 Z018_S04 228 540 0.83 Z011_S03 229 522 0.9 Z011_S03 230 483 0.8  Z011_S03 231 524 0.77 Z011_S03 232 564 1.31Z018_S04 233 510 0.76 Z011_S03 234 538 0.95 Z018_S04 235 497 0.82Z011_S03 236 413 0.60 Z018_S04 237 519 0.68 Z018_S04 238 522 0.66Z018_S04 239 397 0.37 Z018_S04 240 503 0.64 Z018_S04 241 480 0.53Z018_S04 242 425 0.64 Z018_S04 243 494 0.74 Z018_S04 244 407 0.73Z018_S04 245 490 0.56 Z018_S04 246 547 1.05 V012_S01 247 400 0.58X011_S03 248 440 0.97 V011_S01 249 428 0.97 V011_S01 250 428 0.97V011_S01 251 468 1.14 V011_S01 252 522 0.61 X011_S02 253 447 0.67X011_S03 254 395 0.56 004_CA05 255 395 0.55 004_CA05 256 452 0.60004_CA05 257 381 0.5  004_CA05 258 381 0.50 004_CA05 259 455 0.64 n.d.260 438 0.66 Z018_S04 261 438 0.65 Z018_S04 262 438 0.65 Z018_S04 263466 0.65 Z018_S04 264 525 1.19 Z018_S04 265 461 0.59 003_CA04 266 4590.6  003_CA04 267 428 0.61 004_CA07 268 427 0.59 004_CA07 269 442 0.78003_CA04 270 412 0.82 003_CA04 271 426 0.65 n.d. 272 400 1.13 V011_S01273 438 0.73 X011_S03 274 426 0.47 002_CA07 275 486 0.56 002_CA07 276540 0.58 002_CA07 277 504 0.57 Z020_S01 278 490 0.54 n.d. 279 490 0.53Z020_S01 280 413 0.35 X012_S02 281 425 1.03 V011_S01 282 425 1.02V011_S01 283 427 0.49 004_CA07 284 427 0.46 004_CA07 285 422 1.26V011_S01 286 425 0.58 004_CA05 287 467 0.57 004_CA05 288 467 0.64Z018_S04 289 480 0.53 Z018_S04 290 394 1.28 V011_S01 291 448 0.64Z011_S03 292 430 0.51 005_CA01 293 423 0.37 001_CA07 294 405 0.36001_CA07 295 423 0.37 001_CA07 296 441 0.49 X012_S02_(—) 297 421 0.39001_CA07 298 412 0.37 X012_S01_(—) 299 445 0.48 002_CA03 300 423 0.41X012_S01_(—) 301 455 0.47 X012_S01_(—) 302 480 0.53 002_CA03 303 4260.47 X012_S02_(—) 304 421 0.51 002_CA03 305 435 0.48 X012_S01_(—) 306458 0.48 004_CA05 307 430 0.56 004_CA05 308 405 0.35 001_CA07 309 4120.60 004_CA05 310 423 0.73 003_CA04 311 445 0.52 002_CA03 312 417 0.62004_CA05 313 465 0.33 X012_S01_(—) 314 402 0.26 X012_S01_(—) 315 3890.37 X012_S01 316 371 0.31 X012_S01 317 381 0.61 003_CA04 318 386 0.99V011_S01 319 401 0.31 X012_S02 320 397 0.34 X012_S02 321 399 1.10V011_S01 322 405 0.75 003_CA04 323 423 0.55 005_CA01 324 441 0.56005_CA01 325 448 0.53 005_CA01 326 419 0.83 003_CA04 327 384 0.46002_CA07 328 412 0.74 004_CA05 329 468 0.66 X011_S03 330 398 0.8 003_CA04 331 442 0.72 003_CA04 332 439 0.62 X011_S03 333 412 1.15V011_S01 334 502 0.54 Z020_S01 335 372 0.93 V011_S01 336 456 0.67004_CA05 337 441 0.63 X011_S03 338 441 0.29 X018_S02 339 544 0.35X012_S01 340 540 0.83 003_CA04 341 470 0.40 X012_S01_(—) 342 452 0.47004_CA07 343 445 0.48 004_CA07 344 414 0.74 004_CA05 345 428 0.30X012_S01 346 516 0.98 Z011_S03 347 433 0.96 V011_S01 348 468 1.09V011_S01 349 412 1.14 V011_S01 350 415 0.79 003_CA04 351 427 0.57X011_S03 352 413 1.11 V011_S01 353 412 0.78 004_CA05 354 468 0.81003_CA04 355 428 0.90 Z011_S03 356 442 0.91 Z011_S03 357 442 0.93Z011_S03 358 425 0.71 Z012_S04 359 423 1.06 Z011_S03

Examples representing mixtures of stereoisomers can be detected andresolved into single stereoisomers through analytical and preparativechiral chromatography. Representatives of examples for this process aregiven in Table 64

TABLE 64 The abbreviation “Dist. example” refers to the distomer of thegiven example. Analytical SFC Data Prep. Stereoisomer 1 rt Stereoisomer2 rt SFC Example Methode (Exampl No.). [min] (Example No.) [min] Method15 I_ASH_30_10MIN_SS4P.M 2 3.94 Dist.-2 5.67 chiral SFC E 22I_ADH_40_MEOH_DEA.M 29 3.60 Dist.-29 5.76 chiral SFC D 43I_ADH_15_MEOH_DEA.M 249 7.43 250 8.72 chiral SFC C

TABLE 65 List of Abbreviations ACN acetonitrile AIBN2,2′-azobis(isobutyronitrile) ALOX aluminium oxide aq. aqueous BOC tert.butyloxycyrbonyle- d day DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCMdichlormethane DEA diethylamine DIPEA n,n-diisopropylethylamine DIPEdiisopropyl ether DMAP 4-dimethylaminopyridine DMF n,n-dimethylformamideDMSO dimethyl sulfoxide EA ethyl acetate FA formic acid h hour HATUo-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluoro-phosphate LiOH lithium hydroxide MeOH methanol MSAmethanesulfonic acid MeTHF methyl tetrahydrofuran NaH sodium hydride PEpetrol ether RT, r.t. room temperature, e.g. 15-25° C. rt retention timeSI trimethylsilyl iodide TBME tert-butyl methyl ether TBTUo-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′- tetramethyluroniumtetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THFtetrahydrofuran TSA toluene sulfonic acid

Pharmacological Data

Other features and advantages of the present invention will becomeapparent from the following more detailed examples which illustrate, byway of example, the principles of the invention.

Inhibition of Human DPPI (Cathepsin C)

Materials: Microtiterplates (Optiplate-384 F) were purchased fromPerkinElmer (Prod. No. 6007270). The substrate Gly-Arg-AMC was fromBiotrend (Prod.-No. 808756 Custom peptide). Bovine serum albumin (BSA;Prod. No. A3059) and Dithiothreitol (DTT; Prod. No D0632) were fromSigma. TagZyme buffer was from Riedel-de-Haen (Prod.-No. 04269), NaClwas from Merck (Prod.-No. 1.06404.1000) and morpholinoethane sulfonicacid (MES), was from Serva (Prod.-No. 29834). The DPP1 inhibitorGly-Phe-DMK was purchased from MP Biomedicals (Prod.-No. 03DK00625). Therecombinant human DPPI was purchased from Prozymex. All other materialswere of highest grade commercially available.

The following buffers were used: MES buffer: 25 mM MES, 50 mM NaCl, 5 mMDTT, adjusted to pH 6.0, containing 0.1% BSA; TAGZyme Buffer: 20 mMNaH₂PO₄, 150 mM NaCl adjusted to pH 6.0 with HCl

Assay Conditions:

The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1μg/ml, respectively), and then activated by mixing in a 1:2 ratio with aCysteamine aqueous solution (2 mM) and incubating for 5 min at roomtemperature.

Five uL test compound (final concentration 0.1 nM to 100 μM) in aquabidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with10 μL of DPPI in MES buffer (final concentration 0.0125 ng/μL) andincubated for 10 min. Then, 5 μL of substrate in MES buffer (finalconcentration 50 μM) were added. The microtiter plates were thenincubated at room temperature for 30 min. Then, the reaction was stoppedby adding 10 μL of Gly-Phe-DMK in MES-buffer (final concentration 1 μM).The fluorescence in the wells was determined using a Molecular DevicesSpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an EnvisionFluorescence Reader (Ex 355 nm, Em 460 nm).

Each assay microtiter plate contained wells with vehicle controls (1%DMSO in bidest+0.075% BSA) as reference for non-inhibited enzymeactivity (100% Ctl; high values) and wells with inhibitor (Gly-Phe-DMK,in bidest+1% DMSO+0.075% BSA, final concentration 1 μM) as controls forbackground fluorescence (0% Ctl; low values).

The analysis of the data was performed by calculating the percentage offluorescence in the presence of test compound in comparison to thefluorescence of the vehicle control after subtracting the backgroundfluorescence using the following formula:

(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC₅₀ values forinhibition of DPPI, respectively.

TABLE 66 Example Inhibition of DPPI IC50 [μM]  1 0.0086  2 0.0020  30.0007  4 0.0014  5 0.0040  6 0.0107  7 0.0019  8 0.6794  9 0.0096  100.0015  11 0.0017  12 0.0019  13 0.0019  14 0.0020  15 0.0020  16 0.0026 17 0.0026  18 0.0027  19 0.0028  20 0.0031  21 0.0031  22 0.0033  230.0037  24 0.0037  25 0.0039  26 0.0040  27 0.0040  28 0.0041  29 0.0042 30 0.0042  31 0.0043  32 0.0045  33 0.0045  34 0.0046  35 0.0046  360.0047  37 0.0047  38 0.0048  39 0.0051  40 0.0051  41 0.0053  42 0.0053 43 0.0056  44 0.0059  45 0.0063  46 0.0069  47 0.0072  48 0.0072  490.0073  50 0.0074  51 0.0075  52 0.0076  53 0.0079  54 0.0082  55 0.0082 56 0.0083  57 0.0083  58 0.0084  59 0.0085  60 0.0087  61 0.0087  620.0091  63 0.0093  64 0.0093  65 0.0094  66 0.0094  67 0.0096  68 0.0097 69 0.0099  70 0.0102  71 0.0108  72 0.0108  73 0.0112  74 0.0114  750.0114  76 0.0117  77 0.0119  78 0.0120  79 0.0120  80 0.0124  81 0.0131 82 0.0131  83 0.0133  84 0.0137  85 0.0140  86 0.0141  87 0.0142  880.0152  89 0.0156  90 0.0160  91 0.0170  92 0.0177  93 0.0183  94 0.0187 95 0.0192  96 0.0198  97 0.0199  98 0.0203  99 0.0211 100 0.0223 1010.0239 102 0.0248 103 0.0249 104 0.0249 105 0.0250 106 0.0259 107 0.0259108 0.0264 109 0.0269 110 0.0286 111 0.0318 112 0.0333 113 0.0364 1140.0367 115 0.0378 116 0.0391 117 0.0396 118 0.0443 119 0.0512 120 0.0556121 0.1565 122 0.1817 123 0.1866 124 0.1869 125 0.2060 126 0.2751 1270.8597 128 2.3930 129 0.0827 130 0.0435 131 0.1387 132 0.0189 133 0.0161134 0.0178 135 0.2857 136 0.0102 137 0.0597 138 0.0145 139 0.0117 1400.0215 141 0.0366 142 0.0631 143 0.0067 144 0.0263 145 0.0538 146 0.0305147 0.0062 148 0.0304 149 0.0387 150 0.0386 151 0.0369 152 0.0021 1530.0038 154 0.0135 155 0.0008 156 0.0006 157 0.0009 158 0.0015 159 0.0016160 0.0017 161 0.0019 162 0.002 163 0.0021 164 0.0023 165 0.0027 1660.0033 167 0.0034 168 0.0037 169 0.0041 170 0.0042 171 0.005 172 0.0052173 0.0055 174 0.0056 175 0.0063 176 0.0066 177 0.0074 178 0.0074 1790.0075 180 0.0077 181 0.0086 182 0.0088 183 0.0088 184 0.0088 185 0.009186 0.0096 187 0.0098 188 0.0098 189 0.0104 190 0.0109 191 0.0112 1920.0113 193 0.0123 194 0.0133 195 0.0147 196 0.0151 197 0.0156 198 0.0158199 0.016 200 0.0165 201 0.0201 202 0.0229 203 0.0233 204 0.0245 2050.0259 206 0.0263 207 0.0291 208 0.0298 209 0.0458 210 0.0494 211 0.0611212 0.2955 213 0.619 214 0.8148 215 0.8819 216 217 0.0037 218 0.0189 2190.0374 220 0.253 221 0.0037 222 0.0022 223 0.0059 224 0.0012 225 0.0008226 0.0009 227 0.0010 228 0.0016 229 0.0017 230 0.0018 231 0.0022 2320.0022 233 0.0022 234 0.0038 235 0.0047 236 0.0016 237 0.0046 238 0.0143239 0.0034 240 0.0061 241 0.0068 242 0.0109 243 0.0048 244 0.0037 2450.0059 246 0.0059 247 0.0084 248 0.0180 249 0.0063 250 0.0042 251 0.0115252 0.0038 253 0.0110 254 0.0020 255 0.0109 256 0.0263 257 0.0399 2580.0079 259 0.0060 260 0.0035 261 0.0042 262 0.0064 263 0.0118 264 0.0170265 0.0627 266 0.0437 267 0.0105 268 0.0111 269 0.0094 270 0.0063 2710.0059 272 0.0068 273 0.0289 274 0.0065 275 0.0330 276 0.0141 277 0.0030278 0.0010 279 0.0055 280 0.0212 281 0.0033 282 0.0037 283 0.0097 2840.0138 285 0.0093 286 0.0389 287 0.0397 288 0.0023 289 0.0025 290 0.0206291 0.0059 292 0.0009 293 0.0013 294 0.0016 295 0.0021 296 0.0029 2970.0032 298 0.0032 299 0.0032 300 0.0038 301 0.0045 302 0.0047 303 0.0050304 0.0060 305 0.0069 306 0.0070 307 0.0072 308 0.0083 309 0.0091 3100.0094 311 0.0099 312 0.0110 313 0.0136 314 0.0140 315 0.0135 316 0.0424317 0.0520 318 0.2120 319 0.0175 320 0.0096 321 0.0568 322 0.0008 3230.0008 324 0.0010 325 0.0013 326 0.0019 327 0.0034 328 0.0042 329 0.0070330 0.0078 331 0.0093 332 0.0129 333 0.0153 334 0.0220 335 0.0245 3360.0245 337 0.0282 338 0.0443 339 0.0013 340 0.0018 341 0.0076 342 0.0013343 0.0045 344 0.0100 345 0.0184 346 0.0010 347 0.0085 348 0.0176 3490.0206 350 0.0386 351 0.0828 352 0.0173 353 0.0065 354 0.0068 355 0.0224356 0.0200 357 0.0338 358 0.0220 359 0.0088 WO09074829; Example 560.0441Determination of Neutrophil Elastase Activity in U937 Cytosolic LysatePreparation after Incubation with Test Compound

Materials:

Optiplate 384F were purchased from PerkinElmer (Prod. No. #6007270). 24well Nunclon cell culture plates (No. 142475) and 96 well plates (No.267245) were from Nunc. Dimethylsulfoxid (DMSO) was from Sigma (Prod.No. D8418). Nonidet-P40 (NP40) was from USBiological to (Prod. No.N3500)

Substrate, specific for Neutrophil elastase, was from Bachem(MeOSuc-Ala-Ala-Pro-Val-AMC; Prod. No. I-1270).

Human neutrophil elastase was from Calbiochem (Prod. No. 324681)

Buffers: Tris-buffer (100 mM Tris; 1M NaCL; pH 7.5)

Tris-buffer+HSA 0.1%; Human Serum Albumin from Calbiochem (Cat#. 126658)Serine-protease buffer (20 mM Tris; 100 mM NaCL; pH 7.5)+0.1% HSASerine protease lysis buffer: 20 mM Tris-HCL; 100 mM NaCl pH 7.5; +0.2%Nonidet-P40;PBS: phosphate buffered saline, without Ca and Mg, from Gibco

Cell Culture:

U937 from ECACC (Cat. No. 85011440) cultured in suspension at 37° C. and5% CO2.Cell density: 0.2-1 Mio. Cells/ml.Medium: RPMI1640 GlutaMAX (No. 61870) with 10% FCS from Gibco

Cell Seeding and Treatment:

Compounds in 100% DMSO were diluted in Medium (-FCS) with 10% DMSO andfurther diluted according to the experiment planned.

20 μl of the compound solution was transferred in the respective wellsof the 24 well plate and diluted with 2 ml cell suspension/wellcontaining 1,105 cells/ml (final concentration of DMSO=0.1%). Compounddilution factor=100

Compounds (up to 7 concentrations) were tested in triplicates with 3wells for the DMSO 0.1% control, incubated for 48 hours without mediumchange at 37° C., 5% CO2 and 95% relative humidity.

Cell Harvesting and Cell Lysate:

Transfer the cell suspension in 2.2 ml Eppendorf cups. Separate cellsfrom medium by centrifugation (400×g; 5 min; RT); discard thesupernatant. Resuspend in 1 ml PBS; centrifugation (400×g; 5 min; RT);wash cells twice with PBS. Add 100 μl Serin lysis buffer (ice cold) tothe cell pellet; resuspend the pellet and store on ice for 15 minutes.Remove debris by centrifugation at 15000×g for 10 min at 4° C. Transfer80-100 μl lysate supernatant in 96 well plate and store immediately at−80° C.

Neutrophil Elastase Activity Assay:

Frozen lysates were thawn at 37° C. for 10 minutes and stored on ice.Protein content was determined with Bradford protein assay. Lysates werediluted to 0.2-0.5 mg/ml protein in serine protease buffer+HSA.

Standard: NE (100 g/ml stocksolution in Tris-buffer; stored at −80° C.)was diluted in Tris-buffer+HSA to 750 ng/ml, and further seriallydiluted 1:2 for the standard curve.

Buffer, blank, standard and lysate samples were transferred into 384well plate

Pipetting Plan

Blank: 5 μl Tris-buffer+10 μl Tris-buffer+HSA+5 μl Substrate

Standard: 5 μl Tris-buffer+10 μl NE (diff. conc.)+5 μl Substrate

Lysate: 5 μl Tris-buffer+10 μl Lysat+5 μl Substrate

The increase in fluorescence (Ex360 nm/Em 460 nm) is determined over 30minutes with a Molecular Device Spectramax M5 Fluorescence Reader.Kinetic Reduction (Vmax units/sec); 4 vmax points. The amount ofneutrophil elastase (ng/ml) is calculated using the standard curve andthe Spectramax software. The result is interpolated to ng/mg lysateprotein using excel formula functions. Percent inhibition in thecompound-treated lysate samples is calculated relative to theDMSO-treated control-sample (100−(compound-sample*100)/control-sample) Atest compound will give values between 0% and 100% inhibition ofneutrophil elastase. IC50 is calculated using Graphpad Prism; nonlinearfitting (log(inhibitor) vs. response—Variable slope). The IC50 value isinterpolated as the concentration of test compound which leads to aneutrophil to elastase activity reduction of 50% (relative to theDMSO-treated control).

TABLE 67 Reduction of NE-activity Example in U937 cells IC50 [μM]  10.0023  2 0.0062  3 0.0029  4 0.0064  6 0.0024  11 0.0087  16 0.0145  290.0088  42 0.0083  43 0.0092 154 0.0046 155 0.0005 156 0.0023 158 0.0088169 0.0091 177 0.0092 178 0.0036 182 0.0081 185 0.0039 187 0.0073 1880.0044 191 0.0033 192 0.0041 193 0.0065 196 0.0053 217 0.0075 223 0.0030224 0.0010 225 0.0028 226 0.0018 227 0.0009 228 0.0046 229 0.0029 2320.0052 234 0.0069 237 0.0096 241 0.0053 245 0.0038 247 0.0080 249 0.0165250 0.0115 253 0.0055 254 0.0305 267 0.0027 268 0.0007 269 0.0055 2700.0014 271 0.0017 272 0.0024 277 0.0036 278 0.0010 279 0.0019 281 0.0019282 0.0034 283 0.0045 284 0.0053 289 0.0039 293 0.0046 294 0.0078 2950.0086 300 0.0089 303 0.0083 319 0.0093 320 0.0037 322 0.0021 323 0.0014324 0.0013 325 0.0047 326 0.0019 328 0.0012 329 0.0025 330 0.0377 3310.0060 332 0.0058 333 0.0047 339 0.0006 340 0.0008 342 0.0247 343 0.0169344 0.0041 345 0.0069 346 0.0068 348 0.0020 349 0.0028 358 0.0037 3590.0029 WO09074829; Example 56 0.1067

Inhibition of Human Cathepsin K

Materials: Microtiterplates (Optiplate-384 F were purchased fromPerkinElmer (Prod. No. 6007270). The substrate Z-Gly-Pro-Arg-AMC wasfrom Biomol (Prod.-No. P-142). L-Cysteine (Prod. No. 168149) was fromSigma. Sodium actetate was from Merck (Prod.-No. 6268.0250), EDTA wasfrom Fluka (Prod.-No. 03680). The inhibitor E-64 was purchased fromSigma (Prod.-No. E3132). The recombinant human Cathepsin K proenzyme waspurchased from Biomol to (Prod. No. SE-367). All other materials were ofhighest grade commercially available.

The following buffers were used: Activation buffer: 32.5 mM sodiumacetate, adjusted to pH 3.5 with HCl; Assay buffer: 150 mM sodiumacetate, 4 mM EDTA, 20 mM L-Cysteine, adjusted to pH 5.5 with HCl,

Assay Conditions:

To activate the proenzyme, 5 μl procathepsin K were mixed with 1 ulactivation buffer, and incubated at room temperature for 30 min.

5 μL test compound (final concentration 0.1 nM to 100 μM) in aqua bidest(containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uLof Cathepsin K in assay buffer (final concentration 2 ng/μL) andincubated for 10 min. Then 5 μL of substrate in assay buffer (finalconcentration 12.5 μM) were added. The plates were then incubated atroom temperature for 60 min. Then, the reaction was stopped by adding 10μL of E64 in assay buffer (final concentration 1 μM). The fluorescencein the wells was determined using a Molecular Devices SpectraMax M5Fluorescence Reader (Ex 360 nm, Em 460 nm).

Each assay microtiter plate contains wells with vehicle controls (1%DMSO in bidest) as reference for non-inhibited enzyme activity (100%Ctl; high values) and wells with inhibitor (E64 in bidest+1% DMSO, finalconcentration 1 M) as controls for background fluorescence (0% Ctl; lowvalues). The analysis of the data was performed by calculating thepercentage of fluorescence in the presence of test compound incomparison to the fluorescence of the vehicle control after subtractingthe background fluorescence:

(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC₅₀ values forinhibition of Cathepsin K, respectively.

Inhibition of Cathepsin K Example IC50 [μM]  23 3.8  24 13.3  25 6.3  263.6  27 3.2  28 2.7  29 1.4  30 3.1  31 7.3  32 3.9  33 4.8  34 2.5  354.4  36 3.0  37 5.1  38 2.9  39 7.8  40 7.8  41 4.7  42 2.9  43 2.2  444.0  45 4.4  46 4.0  47 3.4  48 3.3  49 6.5  50 3.6  51 4.9  52 17.0  534.1  54 4.5  55 3.9  56 4.0  57 2.3  58 11.1  59 2.5  60 12.3  61 10.9 62 3.9  63 6.2  64 4.2  65 11.7  66 4.8  67 4.6  68 7.3  69 2.4  7012.0  71 4.8  72 7.3  73 3.1  74 2.5  75 5.3  76 5.3  77 5.3  78 6.7  793.5  80 4.1  81 4.5  82 5.4  83 5.1  84 4.9  85 3.0  86 6.8  88 8.8  895.4  90 3.5  91 2.5  92 8.2  93 6.9  94 4.9  95 3.6  96 5.5  97 7.9  988.4  99 2.9 100 8.2 101 6.5 102 4.3 103 5.9 104 10.3 105 5.2 106 5.3 1074.7 108 9.4 109 4.5 110 9.8 111 4.3 112 5.6 113 8.3 114 6.8 115 2.3 1167.7 117 2.7 118 3.9 119 4.5 121 5.2 130 10.2 132 12.2 133 19.4 134 6.7136 6.2 138 6.4 139 4.8 140 8.4 141 8.8 143 5.1 144 11.1 145 7.4 146 9.6147 9.7 148 14.6 149 7.6 150 9.3 151 4.8 152 6.1 153 4.4 154 4.6 155 1.0156 7.8 157 7.4 158 9.4 159 3.3 161 10.7 167 6.3 169 5.2 176 13.9 1819.7 182 3.5 185 1.7 186 3.5 190 3.7 193 2.2 199 11.7 200 3.3 201 2.5 2038.4 218 26.0 222 1.7 228 2.0 229 1.6 230 5.9 231 2.4 233 3.0 234 2.9 2353.0 236 1.7 237 1.9 238 9.3 239 2.0 240 9.4 241 2.5 242 2.5 244 2.0 2451.2 247 4.5 249 3.6 250 3.1 252 3.3 253 5.7 254 4.5 259 3.7 260 3.9 2613.8 262 2.8 263 2.1 267 4.7 268 3.8 269 1.7 270 6.1 274 3.5 276 5.5 2781.2 281 1.9 282 1.8 283 3.6 285 8.7 288 2.2 293 2.7 294 2.2 295 4.7296 >30.0 297 12.4 298 17.6 300 23.1 301 19.5 303 22.2 315 >30.0 319 4.5322 1.1 323 0.9 324 0.8 325 2.3 326 1.1 328 7.7 330 6.6 331 1.5 332 6.2333 2.4 343 5.3 344 6.2 345 9.2 346 4.0 348 4.3 349 5.0 358 9.6 359 6.3WO09074829; Example 56 0.4Determination of Metabolic Stability with Human Liver Microsomes

The metabolic degradation of the test compound is assayed at 37° C. withpooled human liver microsomes. The final incubation volume of 100 μl pertime point contains TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5mM), microsomal protein (1 mg/ml) and the test compound at a finalconcentration of 1 μM. Following a short preincubation period at 37° C.,the reactions are initiated by addition of beta-nicotinamide adeninedinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated bytransferring an aliquot into acetonitrile after different time points.Additionally, the NADPH-independent degradation is monitored inincubations without NADPH, terminated at the last time point. The [%]remaining test compound after NADPH independent incubation is reflectedby the parameter c (control) (metabolic stability). The quenchedincubations are pelleted by centrifugation (10,000 g, 5 min). An aliquotof the supernatant is assayed by LC-MS/MS for the amount of parentcompound.

The half-life (t½ INVITRO) is determined by the slope of thesemilogarithmic plot of the concentration-time profile. The intrinsicclearance (CL_INTRINSIC) is calculated by considering the amount ofprotein in the incubation:

CL_INTRINSIC [μl/min/mg protein]=(ln 2/(half-life [min]*protein content[mg/ml]))*1,000.

The half-life (t½ INVITRO) values of selected compounds in the metabolicstability assay described above are listed in the following table

TABLE 69 In vitro stability in human liver microsome incubations Examplet½ [min]  2 >125  3 57  4 >130  5 92  6 >130  9 >120  10 >130  12 >130 14 >130  15 130  16 >130  19 >130  21 >130  22 >130  24 110  28 >130 29 >130  31 90  33 >130  35 >130  40 >130  41 >130  42 >130  43 >130 44 >130  47 84  49 >130  50 >130  52 >130  53 >130  54 >130  55 >130 57 95  58 >130  62 >130  67 89  71 >120  76 84  77 >130  78 130 82 >130  83 >130  86 >130  88 >130  89 >130  90 >130  91 >130  95 >130 96 82  97 >130  98 >130  99 >130 100 >130 102 >130 105 >130 106 >130108 >130 109 >130 110 >130 111 >130 112 >130 114 >130 116 >130 117 >130125 >130 132 >130 136 >130 139 >130 143 >130 147 >130 152 >130 153 110154 >130 155 62 156 95 157 >130 158 >130 159 >130 162 >130 166 94167 >130 169 >130 171 83 176 >130 178 >130 180 >120 181 >130 182 >130183 >130 184 >130 185 >130 188 97 189 >130 190 >130 191 91 192 >130193 >130 194 85 196 >130 199 88 200 >130 201 >130 204 >130 205 >130218 >130 221 >130 222 >130 223 >130 230 >130 231 >130 233 >130 235 >130236 >130 238 110 239 >130 240 110 241 84 242 >130 244 92 245 >130247 >130 248 >130 249 >130 250 >130 252 130 253 >130 254 >130 255 >130258 >130 259 >130 260 >130 261 >130 262 >120 263 >130 266 >130 267 >130268 >130 269 >130 270 >130 271 130 272 >130 274 >125 276 130 277 >130278 >130 281 >130 282 >130 283 >130 284 58 285 >130 288 >130 289 110291 >130 292 94 293 >130 294 >130 295 >130 296 >130 298 105 300 >130 301100 303 >130 305 91 306 >130 307 >130 308 >130 310 >130 313 >130314 >130 315 92 319 >130 320 >130 321 >130 322 >130 323 >130 324 >130325 >130 327 >130 328 >130 330 >130 331 >120 332 100 333 >130 335 >130341 >130 342 >130 343 >130 344 110 345 >130 346 >130 347 >130 348 130349 >130 358 >130 359 >130 WO09074829; Example 56 120

Combinations

The compounds of general formula I may be used on their own or combinedwith other active substances of formula I according to the invention.The compounds of general formula I may optionally also be combined withother pharmacologically active substances. These include,β2-adrenoceptor-agonists (short and long-acting), anti-cholinergics(short and long-acting), anti-inflammatory steroids (oral and topicalcorticosteroids), cromoglycate, methylxanthine,dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors,PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists,PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor(BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, HistamineH4 receptor antagonists, dual Histamine H1/H3-receptor antagonists,PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases asfor example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAPkinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP,inhibitors of the NF-κB signalling pathway as for example IKK2 kinaseinhibitors, to iNOS inhibitors, MRP4 inhibitors, leukotriene biosyntheseinhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors,Non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists,DP1-receptor modulators, Thromboxane receptor antagonists, CCR3antagonists, CCR⁴ antagonists, CCR1 antagonists, CCR5 antagonists, CCR6antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30antagonists, CXCR³ antagonists, CXCR⁴ antagonists, CXCR² antagonists,CXCR¹ antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR³antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphatereceptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosinereceptor modulators as for example A2a-agonists, modulators ofpurinergic receptors as for example P2X7 inhibitors, Histone Deacetylase(HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors,PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-betaconverting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators,HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIPagonists, GABAa receptor antagonist, ENaC-inhibitors,Prostasin-inhibitors, Matriptase-inhibitors, Melanocortin receptor(MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelinantagonists, TNFα antagonists, anti-TNF antibodies, anti-GM-CSFantibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40antibodies, mucoregulators, immunotherapeutic agents, compounds againstswelling of the airways, compounds against cough, VEGF inhibitors,NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinationsof two or three active substances.

Preferred are betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors,5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors,NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinationsof two or three active substances, i.e.:

-   -   Betamimetics with corticosteroids, PDE4-inhibitors,        CRTH2-inhibitors or LTD4-antagonists,    -   Anticholinergics with betamimetics, corticosteroids,        PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists,    -   Corticosteroids with PDE4-inhibitors, CRTH2-inhibitors or        LTD4-antagonists    -   PDE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists    -   CRTH2-inhibitors with LTD4-antagonists.

Indications

The compounds of the invention and their pharmaceutically acceptablesalts have activity as pharmaceuticals, in particular as inhibitors ofdipeptidyl peptidase I activity, and thus may be used in the treatmentof:

1. respiratory tract: obstructive diseases of the airways including:asthma, including bronchial, allergic, intrinsic, extrinsic,exercise-induced, drug-induced (including aspirin and NSAID-induced) anddust-induced asthma, both intermittent and persistent and of allseverities, and other causes of airway hyper-responsiveness; chronicobstructive pulmonary disease (COPD); bronchitis, including infectiousand eosinophilic bronchitis; emphysema; alpha1-antitrypsin deficiency,bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and relateddiseases; hypersensitivity pneumonitis; lung fibrosis, includingcryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias,fibrosis complicating anti-neoplastic therapy and chronic infection,including tuberculosis and aspergillosis and other fungal infections;complications of lung transplantation; vasculitic and thromboticdisorders of the lung vasculature, polyangiitis (Wegener Granulomatosis)and pulmonary hypertension; antitussive activity including treatment ofchronic cough associated with inflammatory and secretory conditions ofthe airways, and iatrogenic cough; acute and chronic rhinitis includingrhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonalallergic rhinitis including rhinitis nervosa (hay fever); nasalpolyposis; acute viral infection including the common cold, andinfection due to respiratory syncytial virus, influenza, coronavirus(including SARS) and adenovirus;2. skin: psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplasticlesions; drug-induced disorders including fixed drug eruptions;3. eyes: blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune, degenerative or inflammatory disorders toaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial;4. genitourinary: nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale);5. allograft rejection: acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease;6. other auto-immune and allergic disorders including rheumatoidarthritis, irritable bowel syndrome, systemic lupus erythematosus,multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison'sdisease, diabetes mellitus, idiopathic thrombocytopaenic purpura,eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndromeand Sazary syndrome;7. oncology: treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumour recurrences, and paraneoplastic syndromes;and,8. infectious diseases: virus diseases such as genital warts, commonwarts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus,molluscum contagiosum, variola, human immunodeficiency virus (HIV),human papilloma virus (HPV), cytomegalovirus (CMV), varicella zostervirus (VZV), rhinovirus, adenovirus, coronavirus, influenza,para-influenza; bacterial diseases such as tuberculosis andmycobacterium avium, leprosy; other infectious diseases, such as fungaldiseases, chlamydia, Candida, aspergillus, cryptococcal meningitis,Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection and leishmaniasis.9. pain: Recent literature data from Cathepsin C-deficient mice point toa modulatory role of Cathepsin C in pain sensation. Accordingly,inhibitors of Cathepsin C may also be useful in the clinical setting ofvarious form of chronic pain, e.g. inflammatory or neuropathic pain.

For treatment of the above-described diseases and conditions, atherapeutically effective dose will generally be in the range from about0.01 mg to about 100 mg/kg of body weight per dosage of a compound ofthe invention; preferably, from about 0.1 mg to about 20 mg/kg of bodyweight per dosage. For Example, for administration to a 70 kg person,the dosage range would be from about is 0.7 mg to about 7000 mg perdosage of a compound of the invention, preferably from about 7.0 mg toabout 1400 mg per dosage. Some degree of routine dose optimization maybe required to determine an optimal dosing level and pattern. The activeingredient may be administered from 1 to 6 times a day.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the active ingredient will be administered atdosages and in a manner which allows a pharmaceutically effective amountto be delivered based upon patient's unique condition.

1. A compound of formula 1

wherein R¹ is independently selected from H, C₁₋₆-alkyl-, halogen, HO—,C₁₋₆-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— andC₁₋₆-alkyl-C(O)HN—; or two R¹ are together C₁₋₄-alkylene; R² is selectedfrom R^(2.1); aryl-; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3); C₅₋₁₀-heteroaryl-; containing one, two, three or fourheteroatoms independently selected from S, S(O), S(O)₂, O and N, whereincarbon atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.1); wherein nitrogen atomsof the ring are optionally and independently from each other substitutedwith one, two or three R^(2.2); wherein a carbon atom of the ring isoptionally substituted with one R^(2.3); a nitrogen atom of the ring isoptionally substituted with one R^(2.4); and C₅₋₁₀-heterocyclyl-;containing one, two, three or four heteroatoms independently selectedfrom S, S(O), S(O)₂, O and N, wherein the ring is fully or partiallysaturated, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or three or fourR^(2.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.2); wherein a carbon atom of the ring is optionally substitutedwith one R^(2.3) or one R^(2.5); a nitrogen atom of the ring isoptionally substituted with one R^(2.4) or R² and R⁴ are together withtwo adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl orheteroaryl, containing one, two or three heteroatoms independentlyselected from S, S(O), S(O)₂, O and N, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.2); R^(2.1) is independently selected from H, halogen, NC—, O═,HO—, H-A-, H-A-C₁₋₆-alkylene-, R^(2.1.1)-A-, C₁₋₆-alkyl-A-,C₃₋₈-cycloalkyl-A-, C₁₋₆-haloalkyl-A-, R^(2.1.1)—C₁₋₆-alkylene-A-,C₁₋₆-alkyl-A-C₁₋₆-alkylene-, C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-,R^(2.1.1)—C₁₋₆-alkylene-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,HO—C₁₋₆-alkylene-A-, HO—C₁₋₆-alkylene-A-C₁₋₆-alkylene-,C₁₋₆-alkyl-O—C₁₋₆-alkylene-A- andC₁₋₆-alkyl-O—C₁₋₆-alkylene-A-C₁₋₆-alkylene- R^(2.1.1) is independentlyselected from aryl-; optionally substituted independently from eachother with one, two or three R^(2.1.1.1); C₅₋₁₀-heteroaryl-; containingone, two, three or four heteroatoms independently selected from S, S(O),S(O)₂, O and N, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1.1.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-; containing one, two, three or fourheteroatoms independently selected from S, S(O), S(O)₂, O and N, whereinthe ring is fully or partially saturated, wherein carbon atoms of thering are optionally and independently from each other substituted withone, two or three or four R^(2.1.1.1); wherein nitrogen atoms of thering are optionally and independently from each other substituted withone, two or three R^(2.1.1.2); R^(2.1.1.1) is independently selectedfrom halogen, HO—, O═, C₁₋₆-alkyl-, C₁₋₆-alkyl-O—, C₁₋₆-haloalkyl-,C₁₋₆-haloalkyl-O— and C₃₋₈-cycloalkyl-; R^(2.1.1.2) is independentlyselected from O═, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,C₁₋₆-alkyl-O—C₁₋₆-alkyl-, H(O)C—, C₁₋₆-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-; R^(2.2) isindependently selected from H-A-C₁₋₆-alkylene-, C₃₋₈-cycloalkyl-,C₁₋₆-alkyl-A-C₁₋₆-alkylene-, C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,C₁₋₆-alkyl-S(O)₂— and C₁₋₆-alkyl-C(O)—, R^(2.1.1)-A-; R^(2.3) and R⁴ aretogether selected from —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—,—N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—, —C(O)O—,—OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, R^(2.3), R^(2.3),—C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—, —C(R^(2.3.2))₂—O—,—O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—, and—N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-; R^(2.3.1) isindependently selected from H, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-;C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and(C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.3.2) is independently selected fromH, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.4)and R⁴ are together selected from —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—,—N(R^(2.4.1))C(O)—, —S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—,—S(O)—, —S(O)₂—, —C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—,—C(R^(2.4.2))₂N(R^(2.4.1))— and —N(R^(2.4.1))C(R^(2.4.2))₂—,—C₁₋₄-alkylene-; and R^(2.4.1) is independently selected from H,C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;R^(2.4.2) is independently selected from H, C₁₋₆-alkyl-,C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.5)and R⁴ are together selected from —C(R^(2.5.1))═, ═C(R^(2.5.1))—, —N═;and R^(2.5.1) is independently selected from H, C₁₋₆-alkyl-,C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R³ is Hor F; R⁴ is independently selected from F, Cl, phenyl-H₂C—O—, HO—,C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-; A is abond or independently selected from —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)—,—N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—, —S(O)(═NR⁵)—N(R⁵)—,—N(R⁵)(NR⁵═) S(O)—, —S(═NR⁵)₂—N(R⁵)—, —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—,—C≡C—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, —S(═NR⁵)—,—S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S ═N—, —(R⁵N═)(O)S—, and —N═(O)(R⁵)S—;R⁵ is independently selected from H, C₁₋₆-alkyl- and NC—; or a saltthereof.
 2. The compound of formula 1, according to claim 1, wherein R¹is R^(1.a) and R^(1.a) is independently selected from H, C₁₋₄-alkyl-, Fand HO—.
 3. The compound of formula 1, according to claim 1, wherein R⁴is R^(4.a) and R^(4.a) is F, Cl, phenyl-H₂C—O—, HO—, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and C₁₋₄-haloalkyl-O—.4. The compound of formula 1, according to claim 1, wherein R⁴ isR^(4.b) and R^(4.b) is F.
 5. The compound of formula 1, according toclaim 1, wherein A is A^(a) and A^(a) is a bond or independentlyselected from —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,—C(O)O—, —OC(O)—, —C(O)—, —S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S—,—N═(O)(R⁵)S— and R⁵ is R^(5.a) and R^(5.a) is independently selectedfrom H, C₁₋₄-alkyl- and NC—.
 6. The compound of formula 1, according toclaim 1, wherein R² is R^(2.1) and R^(2.1) is R^(2.1.a) and R^(2.1.a) isselected from H, halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-,R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromhalogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
 7. The compound offormula 1, according to claim 1, wherein R² is R^(2.d) and R^(2.d) isphenyl; optionally substituted with one, two or three residuesindependently selected from R^(2.1) and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromhalogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
 8. The compound offormula 1, according to claim 1, wherein R² is R^(2.g) and R^(2.g) isselected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromhalogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected fromH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—,R^(2.1.1)-A-.
 9. The compound of formula 1, according to claim 1,wherein R² is R^(2.j) and R^(2.j) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromhalogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl- andC₁₋₄-haloalkyl-O—, C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected fromH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.
 10. The compound of formula 1, according to claim 1,wherein R² is R^(2.m) and R^(2.m) is together with R⁴ and two adjacentcarbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl,containing one, two or three heteroatoms independently selected from S,S(O), S(O)₂, O and N, wherein carbon atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1), wherein possibly available nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.2); and R^(2.1) is R^(2.1.a) and R^(2.1.a) is selectedfrom H, halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromhalogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected fromH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₁₄-alkyl-S(O)₂—, C₁₋₁₄-alkyl-C(O)— andR^(2.1.1)-A-.
 11. The compound of formula 1, according to claim 1,wherein R² is R^(2.n) and R^(2.n) is selected from aryl-, pyrazole,thiophene, furane; wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two, three or fourR^(2.1); wherein possibly available nitrogen atoms of the ring areoptionally and independently from each other substituted with R^(2.2);wherein a carbon atom of the ring is optionally substituted with oneR^(2.3); a nitrogen atom of the ring is optionally substituted with oneR^(2.4); or R^(2.n) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4) and R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from H,halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromhalogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected fromH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-; and R^(2.3) is together with R⁴ a group R^(2.3.a) andR^(2.3.a) is selected from —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—,—N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—, —C(O)O—,—OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—,—N═C—, —C(R^(2.3.2))₂—O—, —O—C(R^(2.3.2))₂—,—C(R^(2.3.2))₂N(R^(2.3.1))—, —N(R^(2.3.1))C(R^(2.3.2))₂— and—C₁₋₄-alkylene-; and R^(2.3.1) is independently selected from H,C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;R^(2.3.2) is independently selected from H, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; andR^(2.4) is together with R⁴ a group R^(2.4.a) and R^(2.4.a) is selectedfrom —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,—S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—, —S(O)₂—,—C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—, —C(R^(2.4.2))₂N(R^(2.4.1))and —N(R^(2.4.1))C(R^(2.4.2))₂— —C₁₋₄-alkylene-; and R^(2.4.1) isindependently selected from H, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-,C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and(C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.4.2) is independently selected fromH, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; andR^(2.5) is together with R⁴ a group R^(2.5.a) and R^(2.5.a) is selectedfrom —C(R^(2.5.1))═, ═C(R^(2.5.1))— and —N═; and R^(2.5.1) isindependently selected from H, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-,C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and(C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.
 12. The compound of formula 1 accordingto claim 1, wherein R¹ is R^(1.b) and R^(1.b) is H; R² is R^(2.q) andR^(2.q) is selected from among the substituents (a1) to (q1)

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other are substituted with R^(2.2); or a saltthereof.
 13. The compound of formula 1 according to claim 1, wherein R²is R^(2.s) and R^(2.s) is Phenyl-R^(2.3), wherein the phenyl ring isoptionally substituted with one or two residues R^(2.1), wherein R^(2.1)is R^(2.1.a) and R^(2.1.a) is selected from H, halogen, NC—, O═, HO—,H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N, and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromhalogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl. and R^(2.s) and R⁴together denote a group (r1),

wherein the N-atom is optionally substituted with —R^(2.2), whereinR^(2.2) is independently selected from H-A-C₁₋₆-alkylene-,C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-A-C₁₋₄-alkylene-,C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-, C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-,R^(2.1.1)-A-C₁₋₆-alkylene-, C₁₋₆-alkyl-S(O)₂—, C₁₋₆-alkyl-C(O)— andR^(2.1.1)-A-; or a salt thereof.
 14. A compound of formula 1′

wherein R¹, R², R³ and R⁴ have the meaning of claim
 1. 15-16. (canceled)17. A pharmaceutical composition comprising a compound of formula 1according to claim 1 or a pharmaceutically acceptable salt thereof. 18.(canceled)
 19. The pharmaceutical composition according to claim 17further comprising a pharmaceutically active compound selected from thegroup consisting of betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors,5-LO-inhibitors, Histamine receptor antagonists, CCR9 antagonists andSYK-inhibitors, NE-inhibitors, MMP9 inhibitors and MMP12 inhibitors, orcombinations of two or three the pharmaceutically active compound.
 20. Amethod of treating asthma and allergic diseases, gastrointestinalinflammatory diseases, eosinophilic diseases, chronic obstructivepulmonary disease, infection by pathogenic microbes, rheumatoidarthritis or atherosclerosis comprising administering to a patient atherapeutically effective amount of a compound according to claim 1.